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Meliaceous Limonoids: Chemistry and Biological Activities ‡ ‡ Qin-Gang Tan ,§ and Xiao-Dong Luo*, ‡ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650204, P.R.China §Guilin Medical University, Guilin, 541004, P.R.China
CONTENTS 5.2.2. Antimicrobial Activity BR 1. Background and Introduction A 5.2.3. Antiprotozoal Activity BR 2. Meliaceous Limonoids and Their Sources E 5.2.4. Others BS Author Information BT 2.1. Ring Intact Limonoids E Biographies BT 2.1.1. Azadirone-Class E Acknowledgment BT 2.1.2. Cedrelone-Class F References BU 2.1.3. Havanensin-Class G 2.1.4. Trichilin-Class H 2.1.5. Vilasinin-Class H 1. BACKGROUND AND INTRODUCTION 2.1.6. Others I The word “limonoids” originated from the bitterness of lemon 2.2. Ring-seco Limonoids I or other citrus fruit. Structurally, limonoids are formed by loss of 2.2.1. Demolition of a Single Ring I four terminal carbons of the side chain in the apotirucallane or apoeuphane skeleton and then cyclized to form the 17β-furan 2.2.2. Demolition of Two Rings M ring, and thus limonoids are also known as tetranortriterpenoids. 2.2.3. Demolition of Three Rings (Rings Limonoids in the plant kingdom occur mainly in the Meliaceae A,B,D-seco Group) R and Rutaceae families and less frequently in the Cneoraceae.1 2.3. Rearranged Limonoids R With 50 genera and more than 1400 species, Meliaceae are distributed in tropical and subtropical regions throughout the 2.3.1. 1,n-Linkage Group R world.2 As the characteristic natural products of the Meliaceae, 2.3.2. 2,30-linkage Group T limonoids have attracted considerable interest within the chemi- 2.3.3. 8,11-Linkage Limonoids (Trijugin-Class) AA cal and biological research communities. The neem tree 2.3.4. 10,11-Linkage Limonoids (Azadirachta indica), one of the most famous limonoid produ- (Cipadesin-Class) AA cing plants in Meliaceae, has long been recognized as a source of environment-friendly biopesticide. Azadirachtin (292), a com- 2.3.5. Other Linkages Group AB plex limonoid from neem seed kernel, is the main component 2.4. Limonoids Derivatives AC responsible for the toxic effects on insects. The commercial 2.4.1. Pentanortriterpenoids, Hexanortriterpe- application of the limonoids in the agricultural industry has noids, Heptanortriterpenoids, Octanor- enjoyed significant growth in recent decades. Commercial neem triterpenoids, and Enneanortriterpenoids products (seed kernel extract of A. indica), such as Margosan-O, Azitin, Turplex, and Align were granted approval for pest control Derivatives AC usage in the United States by the EPA.3 5 Furthermore, A. indica 2.4.2. Simple Degraded Derivatives AD was also introduced and has been planted on a large scale in 2.4.3. N-Containing Derivatives AD Yunnan province, P. R. China since the 2000s (Figure 1). Three 3. Chemotaxonomic Significance of Meliaceous commercial limonoids products (extracts of A. indica, Melia Limonoids AD toosendan, and M. azedarach), known as biorational insecticides, 4. Synthesis of Meliaceous Limonoids AF were also granted approval in China for insect control on organic 5. Biological Activities of Meliaceous Limonoids AV vegetable plantings. In a pharmaceutical application from China, a formulation with toosendanin, a limonoid from M. toosendan 5.1. Biological Activities in Agricultural Use AW that displays dramatic antibotulismic effects, was developed as a 5.1.1. Insects Antifeeding Activity AW commercial product from TCM (Traditional Chinese Medi- 5.1.2. Insects Growth Regulatory Activity BC cine), where it has been used as an anthelmintic vermifuge 5.1.3. Insecticidal Activity BL against ascarids for a long time.6 5.1.4. Antiphytopathogen Activity BM Some mini-reviews related to limonoids from Meliaceae have 7 13 5.1.5. Others BM been presented since 1966. For example, the chemistry, 5.2. Biological Activities in Medicinal Use BP Received: December 14, 2009 5.2.1. Antineoplastic Activity BP
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biosynthesis,1,13 15 and biological activities16 18 of meliaceous insect-growth-regulating activity,25,28,29 as well as its environ- limonoids were summarized in different years. It is noteworthy mental behavior,19 and its physiological behavior properties.30,31 that some reviews emphasize the well-known azadirachtin (292) In addition, the toxicity characteristics of azadirachtin and the and aspects of its chemistry,19 22 synthesis,23,24 and bioactivities mechanisms of its insecticidal action32 35 were also reviewed. including antifeedant activity,25 27 insecticidal activity,25 and Reviews on the chemistry and biological activities of limo- noids from Azadirachta indica,36 43 Melia azedarach, and M. toosendan37,44 47 have been presented. Moreover, some other reviews related to meliaceous limonoids have also been pub- lished, such as those on the chemistry of cedrelone (81),48 the biological activity of gedunin (416),49 and the occurrence, biosynthesis, biological activity, and NMR spectroscopy of D and B,D-ring seco-limonoids from Meliaceae.50 However, none of them gave general insight into the chemistry and biological Figure 1. Azadirachta indica at Yuanmou county, Yunnan Province, activities of meliaceous limonoids. P. R. China. (A) Neem seedlings were bred on a large scale. (B) Neem trees During our investigations on the biologically active consti- were cultivated at both sides of the road. (C) Four-year-old neem trees tuents of Meliaceae, we noticed confusion and ambiguity about produced plenty of fruit. Photographs courtesy of Dr. Yanping Zhang. limonoids in the literature. (i) Some limonoids structures were
Figure 2. Proposed major biosynthesis routes and classification of meliaceous limonoids.
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Table 1. Structures and Sources of Azadirone-Class Limonoids 1 80
no. compounds substitution groups and others sources
57 59,80 83 1 azadirone R1 =R3 =R4 =R5 =H;R2 =Ac Azadirachta indica; Entandrophragma delevoyi;75 Melia toosendan;76,84,85Trichilia havanensis;86Turraea robusta;87 Khaya anthotheca60 88 2 7-deacetoxy-7-hydroxyazadirone R1 =R2 =R3 =R4 =R5 =H Walsura piscidia α 60 3 11 -acetoxyazadirone R1 =R4 =R5 =H;R2 = Ac, Khaya anthotheca α R3 = -OAc β 60,89 4 11 -acetoxyazadirone R1 =R4 =R5 =H;R2 = Ac, K. anthotheca β R3 = -OAc α 90 5 12 -acetoxy-7-deacetylazadirone R1 =R2 =R3 =R5 =H;R4 = OAc Turraesa cornucopia 91 6 chisosiamensin R1 =R3 =R4 =R5 =H; Chisocheton siamensis Δ5,6 R2 = Ac; α 61,62,64,92 7 nimonol (nimocinol) R1 = -OH; R2 = Ac; R3 = Azadirachta indica
R4 =R5 =H α α 93 8 6 -O-acetyl-7-deacetylnimocinol R1 = -OAc; R2 =R3 =R4 = A. indica
R5 =H α α 69,94 96 9 6 -acetoxyazadirone (paniculatin) R1 = -OAc; R2 = Ac; R3 = Chisocheton paniculatus; 75 R4 =R5 =H Entandrophragma delevoyi 80 10 nimocin R1 =R3 =R4 =R5 =H;R2 =Bz Azadirachta indica β 66 11 dysobinin R1 = -OAc; R2 = Ac; R3 =R4 = Dysoxylum binetariferum; 91,97 R5 =H Chisocheton siamensis 91,97 98 12 azadiradione R1 =R3 =R4 =H;R2 = Ac; R5 =O C. siamensis; Cedrela odorata; Quivisia papinae;99Lansium domesticum;100 Azadirachta indica57,58,70,80 82,101 108 101,109,110 13 nimbocinol (7-deacetylazadiradione) R1 =R2 =R3 =R4 =H;R5 =O A. indica 68,70 14 7-desacetyl-7-benzoylazadiradione R1 =R3 =R4 =H;R2 = Bz; R5 =O A. indica (7-benzoylnimbocinol) α α 99 15 7-deacetyl-7-angeloyl-6 -hydroxyazadiradione R1 = -OH; R2 = Ang; R3 = Quivisa papinae
R4 =H;R5 =O α α 99 16 6 -hydroxyazadiradione R1 = -OH; R2 = Ac; R3 =R4 =H; Q. papinae
R5 =O α α 69 17 6 -acetoxy-16-oxoazadirone (mahonin) R1 = -OAc; R2 = Ac; R3 =R4 =H; Chisocheton paniculatus; 71,111,112 R5 =O Swietenia mahagoni β 113 18 17 -hydroxyazadiradione R1 =H;R2 =Ac Carapa guianensis; Azadirachta indica70,81,103,104,109,114 116 β 101,107 19 7-deacetyl-17 -hydroxyazadiradione R1 =R2 =H A. indica α β 94,117 20 6 -acetoxy-17 -hydroxyazadiradione R1 = OAc; R2 =Ac Chisocheton paniculatus 70 21 7-benzoyl-17-hydroxynimbocinol R1 =H;R2 =Bz Azadirachta indica 22 15-hydroxyazadiradione A. indica70 23 7-acetyl-16,17-dehydro-16- A. indica70 hydroxyneotrichilenone 118 24 isonimolide R1 = OCH3;R2 = Ac; R3 = A. indica
R4 =R5 =H;R6 = OH; R7 =O 118 25 isolimbolide R1 =R5 =H;R2 = Ac; R3 = OAc; A. indica
R4 =R6 = OH; R7 =O 80 26 nimocinolide R1 =R7 = OH; R2 = Ac; R3 = A. indica
R4 =R5 =H;R6 =O 119 27 23-O-methylnimocinolide R1 = OH; R2 = Ac; R3 =R4 = A. indica
R5 =H;R6 =O;R7 = OCH3 α 119,120 28 7-O-deacetyl-23-O-methyl-7 - R1 = OH; R2 = Sen; R3 =R4 =R5 =H; A. indica
O-senecioylnimocinolide R6 =O;R7 = OCH3 80,118 29 isonimocinolide R1 =R6 = OH; R2 = Ac; R3 =R4 =R5 =H; A. indica
R7 =O
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Table 1. Continued no. compounds substitution groups and others sources 121 30 nimbocinolide R1 =R5 =H;R2 = Ac; R3 = OiBu(OH); A. indica
R4 =R7 = OH; R6 =O 122 31 isonimbocinolide R1 =R5 =H;R2 = Ac; R3 = OiBu(OH); A. indica
R4 =R6 = OH; R7 =O 92 32 meliacinanhydride R1 = OH; R2 = Ac; R3 = OCH3;R4 = OAc; A. indica
R5 =H;R6 =R7 =O 120 33 22,23-dihydronimocinol R1 = OH; R2 = Ac; R3 =R4 =R5 =R6 = A. indica Δ20,21 R7 = H; 22,23-dihydro; 123 34 azadironolide R1 =R3 =R4 =R5 =H;R2 = Ac; R6 =O; A. indica
R7 =OH 124 35 O-methylazadironolide R1 =R3 =R4 =R5 =H;R2 = Ac; R6 =O; A. indica
R7 = OCH3 α 125 36 12 -acetoxyazadironolide R1 =R3 =R5 =H;R2 = Ac; R4 = OAc; Turraea parvifolia
R6 =O;R7 =OH 70 37 23-deoxyazadironolide R1 =R3 =R4 =R5 =R6 =H; Azadirachta indica
R2 = Ac; R7 =O 123 126 38 isoazadironolide R1 =R3 =R4 =R5 =H;R2 = Ac; A. indica; Turraea pubescens
R6 = OH; R7 =O 70,123,127 39 azadiradionolide R1 =R3 =R4 =R7 =H;R2 = Ac; Azadirachta indica
R5 =R6 =O 128 40 salimuzzalin R1 =R2 =R3 =R4 =R5 =H; A. indica
R6 =R7 = OAc 125 41 turraparvin A R1 =R2 =R3 =R5 =H;R4 = OAc; Turraea parvifolia
R6 =O;R7 =OH 125 42 turraparvin B R1 =R2 =R3 =R5 =H;R4 = OAc; T. parvifolia
R6 = OH; R7 =O 125 43 turraparvin C R1 =R3 =R5 =H;R2 = Ac; R4 = OAc; T. parvifolia
R6 = OH; R7 =O 117 44 R1 = OAc; R2 = Ac; R3 =R4 =R5 =H; Chisocheton paniculatus
R6 = OH; R7 =O α 129 45 7 ,23-dihydroxy-3-oxo-24,25,26,27- R1 =R2 =R3 =R4 =R5 =H;R6 =O; Trichilia estipulata
tetranortirucall-1,14,20(22)- R7 =OH trien-21,23-olide α 79 46 limocin A R1 =R4 =H;R2 = Ac; R3 = -OCH3 Azadirachta indica 79 47 limocin B R1 =R3 =H;R2 = Ac; R4 = OCH3 A. indica 130 48 23-desmethyl limocin B R1 =R4 =H;R2 = Ac; R4 =OH A. indica 127 49 limocin C R1 =R4 =H;R2 = Ac; R3 = OCH2CH3 A. indica 127 50 limocin D R1 =R3 =H;R2 = Ac; R4 = OCH2CH3 A. indica α 70 51 limocin E R1 =R3 =H;R2 = Ac; R4 = -OCH3 A. indica β 70 52 23-epilimocin E R1 =R3 =H;R2 = Ac; R4 = -OCH3 A. indica 131 53 R1 =R2 =R3 =H;R4 =O Chisocheton microcarpus 117 54 R1 = OAc; R2 = Ac; R3 =H;R4 =O C. paniculatus 117 55 R1 = OAc; R2 = Ac; R3 =H;R4 =OH C. paniculatus 131 98 56 20,21,22,23-tetrahydro-23-oxoazadirone R1 =R3 =H;R2 = Ac; R4 =O C. microcarpus; Cedrela odorata; C. fissilis;132Azadirachta indica70 133 57 meliatoosenin A R1 =R3 =H;R2 =R4 =O Melia toosendan 133 58 meliatoosenin B R1 =R2 =R3 =H;R4 = O; 1,2-dihydro M. toosendan 59 isonimolicinolide Azadirachta indica72 57,58,70,73,78,80 82,103 106,115,134 136 60 nimbinin (epoxyazadiradione) R1 =R3 =R4 =H;R2 = Ac; R5 =O A. indica; Carapa guianensis;137 Entandrophragma delevoyi;75 Chisocheton siamensis91 68,70 61 7-desacetyl-7-benzoylepoxyazadiradione R1 =R3 =R4 =H;R2 = Bz; R5 =O Azadirachta indica α 137 91,138 62 6 -acetoxyepoxyazadiradione R1 = OAc; R2 = Ac; R3 =R4 =H;R5 =O Carapa guianensis; Chisocheton siamensis 139 63 14,15-epoxynimonol R1 = OH; R2 = Ac; R3 =R4 =R5 =H Azadirachta indica
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Table 1. Continued no. compounds substitution groups and others sources 76,84 124 64 trichilenone acetate R1 =R3 =R4 =R5 =H;R2 =Ac Melia toosendan; Azadirachta indica; (14β,15β-epoxyazadirone; acetyltrichilenone) Trichilia havanensis;74Entandrophragma delevoyi75 α β β 75 140 65 6 -acetoxy-14 ,15 -epoxyazadirone R1 = OAc; R2 = Ac; R3 =R4 =R5 =H E. delevoyi; Toona ciliata; Chisocheton paniculatus94 77 66 heudelottin C R1 =R5 =H;R2 = iVal(OH); R3 = OH; Trichilia heudelottii
R4 = O-2-acetoxy-3-methylpentanoyl 77,141 67 heudelottin E R1 =R5 =H;R2 = iVal(OH); R3 = OCHO; T. heudelottii
R4 = O-2-hydroxy-3-methylpentanoyl 77 68 heudelottin F R1 =R5 =H;R2 = iVal(OH); R3 = OCHO; T. heudelottii
R4 = O-2-acetoxy-3-methylpentanoyl α β β Δ5,6 142 69 6-acetoxy-7 -hydroxy-3-oxo-14 ,15 - R1 = OAc; R2 =R3 =R4 =R5 =H; Melia azedarach epoxymeliace-1,5-diene 68 70 7-acetoxyneotrichilenone R1=R3 =H;R2 =Ac Azadirachta indica α fl 143 71 12 -acetoxyneotrichilenone R1 =R2 =H;R3 = OAc; Turraea oribunda 144 72 walsurin R1 =O;R2 =R3 =H Walsura yunnanensis 145 73 toonaciliatone A R1 = OH; R2 =R3 =H Toona ciliata 129 74 7-deacetyl-21-hydroxyneotrichilenonelide R1 = OH; R2 =O Trichilia estipulata 129 75 7-deacetyl-23-hydroxyneotrichilenonelide R1 =O;R2 =OH T. estipulata 110,146 76 17-epinimbocinol R1 =R2 =H Azadirachta indica 70,103,104,114 77 17-epiazadiradione R1 = Ac; R2 =H A. indica 70,107 78 17-epi-17-hydroxyazadiradione R1 = Ac; R2 =OH A. indica 79 vepinin A. indica78 80 limocinin A. indica79 assigned incorrectly because of the lack of the advanced spectral the loss of four carbons to form the 17 β-furan ring. That the methods, such as 2D-NMR, HRMS, in the early time. For latter step is accomplished after the formation of the 4,4,8- example, even though azadirachtin (292) was found early in trimethyl-steroid skeleton is indicated by the occurrence of 1968,51 its structure was revised several times before the final several protolimonoids. Followed formation of the basic limo- unambiguous assignment was made in 1986.52 (ii) On one hand, noid skeleton, a variety of oxidations and skeletal rearrangements some limonoids were given the same nomenclature but had can occur and lead to various classes of limonoids (Figure 2),17 different structures, such as cipadesin D being used for both which will be discussed in detail in this review. compound 57853 and 103854 even though they were ascribed to 2.1. Ring Intact Limonoids different classes. On the other hand, some limonoids have the ff 2.1.1. Azadirone-Class. Azadirone-type limonoids are char- same structure but di erent names. Taking compound 805 as an 1,2 1 fi acteristic of 3-oxo-Δ and C-7 oxygenation. In their H NMR example, it was rst reported as 8,30-epoxy swietenine acetate in δ 198355 and subsequently mistaken as swietemahonin F in 1990.56 spectroscopy, the chemical shifts of H-1 and H-2 were 7.0 7.2 and 5.7 6.0, respectively, which showed the coupling constant This review is an extensive coverage of all naturally occurring ∼ 13 α β limonoids from Meliaceae discovered in the last six decades of 10 Hz. In their C NMR spectroscopy, the , -unsaturated ketone system exhibited signals of δ = 156 160 (C-1), 124 127 (from 1942 to June 30, 2010) along with their various bioactiv- ities. The distribution, chemotaxonomy significance, synthesis, (C-2), and 202 205 (C-3), respectively. The signal of H-7 (δ 5.2 5.4) might shift by 0.1 0.2 ppm and the signal of C-7 and biological activity of meliaceous limonoids are summarized. ∼δ In the cases where sufficient information is available, the structure ( 70 75) shifts to 75 83 ppm if C-6 is oxygenated. Azadirone (1) was first isolated from oil of Azadirachta indica activity relationship (SAR) and the mode of action of the active 57 58 limonoids have been presented. Furthermore, we try to clarify the in 1967, and its structure was later elucidated in 1971. It was also obtained from a rare stem exudation of A. indica, together confusing trivial names in meliaceous limonoid investigations. 59 However, limonoids whose names were not proposed by their with nimbin (391) and gedunin (416). The interrelationship discoverers (44, 53 55, 119, 125-127, 231, 457, 511, 563, 602, between azadirone (1), azadiradione (12), and nimbinin (60) 607,and844) were presented only with numbers in the tables. was analyzed in terms of a possible chemical degradation through a stepwise oxidation and transformation in nature.58 The relative stereochemistry of 11α- and 11β-acetoxyazadirone (3 and 4) was 2. MELIACEOUS LIMONOIDS AND THEIR SOURCES assigned from the downfield shift of the angular methyl groups at Limonoids are supposed to arise from Δ7-tirucallol (20S)or C-8 and C-10, in which the shifts in the 11β-isomer were more Δ7-euphol (20R). The Δ7-bond is epoxidized and is then opened strongly influenced by the acetate function.60 inducing a Wagner Meerwein shift of Me-14 to C-8, which leads The structure corresponding to 7 was assigned to be to the formation of the OH-7 and the introduction of a double nimonol61,62 and confirmed by crystal analysis63 despite once bond at C-14/15. This scheme account for both the ubiquitous having been mistaken to be nimocinol.64 Photooxygenation of presence of oxygen at C-7 and the correct stereochemistry of the nimonol (7) yielded a novel product, 14,15,20,21-diepoxy-23- C-30 methyl group. Subsequently the side chain is cyclized with nimonolactone, and involved interesting Diels Alder and ene
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Figure 3. Structures of azadirone-class limonoids 1 80. reactions. This was the first example of the photolysis of intact were distinguished by the 7α,15β-epoxy ring of the former and limonoids in the absence of a sensitizer and of the epoxidation of the OH substitution at C-20 of the latter. the D-ring with an α stereochemistry under photolysis.65 The 2.1.2. Cedrelone-Class. The cedrelone-class limonoids are structure of dysobinin (11) was elucidated on the basis of characterized as the 5,6-enol-7-one derivatives. The 13C NMR chemical evidence66 and then confirmed by X-ray diffraction.67 spectra showed signals of δ = 132 135 (C-5), 140 143 (C-6), 7-Desacetyl-7-benzoylazadiradione (14)68 and 6α-acetoxy-16- and 196 199 (C-7). The UV spectra showed the absorption at oxoazadirone (17)69 were mistaken for 7-benzoylnimbocinol70 277 nm (in EtOH) from the diosphenol chromophore. and mahonin,71 respectively. Isonimolicinolide (59), the first The molecular formula of cedrelone (81), the principal fi 147 limonoid with an acetoxy function at C-17, might be regarded as constituent of Cedrela toona, was rst assigned as C25H30O5, a possible intermediate in the biosyntheses of 17β-hydroxy- and later was revised to be C H O based on chemical and 26 30 5 azadiradione (18) and nimolicinol (451).72 Compound 60 was mass spectroscopic work.148 151 Its structure was finally con- obtained and named as epoxyazadiradione57 and nimbinin73 by firmed by X-ray diffraction.152 Furthermore, the X-ray study of two separate research groups in 1967. The structure correspond- cedrelone iodoacetate proved its biosynthetic relationship to ing to 64 was first named as trichilenone acetate early in 1973,74 limonin.148,153 On the basis of the HMBC and DEPT experi- and mistaken for 14β,15β-epoxyazadirone in 199475 and acetyl- ments, the signals for C-9, -11, -12, -17, -21, -23, and -28 of 81 trichilenone in 1995,76 when it was isolated from different plants. were reassigned.154 The chemistry of 81 was reviewed in some Heudelottins E and F (67 and 68) were of interest because detail by Govindachari in 1968.48 The structure of one of the they were the simplest limonoids containing the 11β-formyloxy- photooxidation product of 81, in particular the product with 12α-(2-hydroxy-3-methylvaleryloxy) system, which had been epoxy lactone, was established by NMR data and confirmed by found very commonly in the complex A,B-seco limonoids of X-ray crystallography.155 prieurianin class.77 Three 17-epi isomers 76-78 obtained from In the course of model experiments with anthothecol (84) A. indica were rare in limonoids from Meliaceae. Vepinin (79)78 aimed at structural correlation with 11β-acetoxyazadirone (4), and limocinin (80),79 two unique compounds from A. indica, aZn Cu couple was found in the meliacin series to be a
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Table 2. Structures and Sources of Cedrelone-Class Limonoids 81 105
no. compounds substitution groups and others sources
147,158 160 154,161 81 cedrelone R1 =R2 =H Cedrela toona; Toona ciliata; T. australis;162 Khaya anthotheca;163,164 Trichilia catigua;165 Walsura yunnanensis144 β β 144 82 11 -hydroxycedrelone R1 = -OH; R2 =H W. yunnanensis β α β α 143 83 11 ,12 -diacetoxycedrelone R1 = -OAc; R2 = -OAc Turraea holstii α 60,89,163,164,166 168 84 anthothecol R1 = -OAc; R2 =H Khaya anthotheca α 89,163 85 deacetylanthothecol R1 = -OH; R2 =H K. anthotheca 154 86 23-hydroxycedrelonelide (walsuranolide) R1 =H;R2 =O;R3 =OH Toona ciliata; Walsura yunnanensis144 β 144 87 11 -acetoxywalsuranolide R1 = OAc; R2 =O;R3 =OH W. yunnanensis 144 88 20,22-dihydro-22,23-epoxywalsuranolide R1 =H;R2 = O; 20,22- W. yunnanensis dihydro; 22,23-epoxy 144 89 21-hydroxycedrelonelide (isowalsuranolide) R1 =H;R2 = OH; R3 =O W. yunnanensis; Toona ciliata154 90 1,2-dihydrocedrelone R = H Cedrela toona158 91 11β-hydroxydihydrocedrelone R = β-OH Walsura yunnanensis144 92 11β-acetoxydihydrocedrelone R = β-OAc W. yunnanensis144 93 1α,l1:14β,15β-diepoxy-6-hydroxymeliaca-5,9,20,22-tetraene-3,7-dione Khaya anthothea60 169,170 171 94 hirtin R1 = Ac; R2 = propanoyl Trichilia hirta; T. pallida 169 171 95 deacetylhirtin R1 =H;R2 = propanoyl T. hirta; T. pallida β α 171 96 methyl 6-hydroxy-11 -acetoxy-12 -(2-methylpropanoyloxy)-3, R1 = Ac; R2 = iBu T. pallida 7-dioxo-14β,15β-epoxy-1,5-meliacadien-29-oate β α 171 97 methyl 6,11 -dihydroxy-12 -(2-methylpropanoyloxy)-3, R1 =H;R2 = iBu T. pallida 7-dioxo-14β,15β-epoxy-1,5-meliacadien-29-oate β α 171 98 methyl 6-hydroxy-11 -acetoxy-12 -(2-methylbutanoyloxy)-3, R1 = Ac; R2 = Piv T. pallida 7-dioxo-14β,15β-epoxy-1,5-meliacadien-29-oate 99 methyl 11β-acetoxy-6-hydroxy-12α-(2-methylpropionyloxy)-3, T. hirta172 7-dioxo-1,5,14,20,22-meliacapentaen-29-oate 100 methyl 11β-acetoxy-6,23-dihydroxy-12α-(2-methylpropionyloxy)-3, T. hirta172 7,21-trioxo-1,5,14,20,22-meliacatetraen-29-oate α f β 173 101 azecin 3 R1 = -L-Rha-(1 4)- -D- Melia azedarach f β Glc-(1 6)- -D-Glc; R2 =H β β β 174 102 6,11-diacetoxy-7-oxo-14 ,15 -epoxymeliacin-1,5-diene- R1 = -D-Glc; R2 = OAc M. azedarach 3-O-β-D-glucopyranoside β β β β 175 103 6-acetoxy-3 -hydroxy-7-oxo-14 ,15 -epoxymeliac-1,5-diene- R1 = -D-Xyl; R2 =H M. azedarach 3-O-β-D-xylopyranoside α β β α 176 104 6-acetoxy-11 -hydroxy-7-oxo-14 ,15 -epoxymeliacin-1, R1 = -L-Rha; R2 =OH M. azedarach 5-diene-3-O-α-L-rhamnpyranoside β β β β 142 105 6-acetoxy-3 -hydroxy-7-oxo-14 ,15 -epoxymeliac-1,5-diene-3- R1 = -D-glucuronic acid; M. azedarach β O- -D-glucuronopyranoside R2 =H convenient and superior reagent for the reduction of epoxides to 9,11-double bond, the enol ether group of was stable to both acid olefins, α,β-unsaturated ketones to saturated ketones, and ketols and base. This unreactivity was probably because of steric and their acetates to ketones.89 Burke et al. presented the hindrance to attack on the enol system.60 chemical correlation of 84 with hirtin (94), which differ in 2.1.3. Havanensin-Class. The havanensin-class limonoids oxidation status at C-29.156 Walsuranolide and isowalsuranolide bear oxygenic substituent at C-1, C-3, and C-7, and the degree of reported by Luo et al. in 2000144 were actually 23-hydroxyce- oxidation at C-28 varies from methyl to carboxyl. Under mildly drelonelide (86) and 21-hydroxycedrelonelide (89) isolated in acid conditions, the first stage of the ring-opening of havanensin 1994,154 respectively, whose structures were introduced incor- (106) gives a 15-hydroxy-14-carbonium ion, which then either rectly as 30-nor (C-8 Methyl) derivatives by Chemical Abstracts undergoes Wagner Meerwein rearrangement or loses a proton (CA, 1994). In the crystal structure which was established for 1,2- to give a 15-ketone enolate and involves participation of the dihydrocedrelone (90), the rings A, B, C, and D adopted sofa, oxygenated function at C-7.177 Grandifolione (112) was the first half-chair, twist and envelope conformations, respectively.157 In natural representative of a stage regarded as intermediate in 1α,11:14β,15β-diepoxy-6-hydroxymeliaca-5,9,20,22-tetraene-3,7- the in vivo transformation of apo-euphol (or apo-tirucallol) dione (93), an unusual compound with a 1,11-ether and a into the typical pentenolide system found in limonoids.178
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Figure 4. Structures of cedrelone-class limonoids 81 105.
14,15-Deoxyhavanensin 3,7-diacetate (114) and deoxyhavanensin 156 derived from that precursor should be an epimer mixture of triacetate (115) isolated from the unripened seeds of Trichilia the hemiacetal.201 The structure of 28-deacetylsendanin referred havanensin revealed a lower degree of oxidation of the limonoid to in some literature202 204 should in fact be 29-deacetylsenda- skeleton and could be viewed as the biosynthetic precursors of the nin (157),205 which was isolated as a 5:3 mixture of epimer with limonoids isolated from the mature seeds.86 Sendanal (122)wasof respect to C-29.206 In fact, the structure of compound 29- biosynthetic interest from the viewpoint that it was closely related isobutylsendanin205 obtained from Melia azedarach in 1995 was to a precursor of the 14,15-epoxy-12-hydroxy moiety, which could the same as 12-O-acetylazedarachin B (161)207 found in 1994 in yield limonoids of the nimbin class through a Grob fragmentation the same species. Meliartenin (164) was shown to be a mixture of followed by formation of an ether ring between the C-7 and C-15 two interchangeable isomers.208 Huang et al. mistook compound 209 hydroxyl groups via an SN1 mechanism. The co-occurrence of 122 166 as 12-deacetyltoosendanin when citing its origin, in which it and ohchinal (343) in the same tree provided a piece of evidence was in fact named as 12α-hydroxyamoorastatin.210 The structure for such pathway.179 Unfortunately, limonoids 131 134 isolated of toosendanin211,212 and 12α-acetoxyamoorastatin213,214 was in by Torto et al. were named mistakenly as 28-nor-4α-carbomethoxy fact proved to be identical with that of chuanliansu (167), which was derivatives of havanensin (106). However, C-28 of 131 134 first assigned in 1975215 and subsequently corrected in 1980.216 was present and so numbered in the original paper, and 131 was Based on the observation of a significant difference in the chemical confirmed by X-ray diffraction.180 shift between 3α-deacetylamoorastatin (168, δ C-9: 39.5) and 9β- 2.1.4. Trichilin-Class. The trichilin-class limonoids mostly amoorastatin (169, δ C-9: 48.2), Vardamides et al. proposed the originated from genera Melia and Trichilia (Table 4), and stereochemistry of H-9 as β in 169.217 The biosynthetic formation contained the C-19/29 lactol bridge and the 14,15-epoxide of 7,14-epoxyazedarachin B (183) could presumably be explained moieties except in compounds 172 185. The 13C NMR spectral by an intramolecular nucleophilic attack of the hydroxyl group on assignments for trichilin A (135) were revised based on 2D- the C-14 position of the epoxide ring, and in contrast a preferable NMR data in 1998.192 Treatment of 135 with zinc borohydride alternative route led to neoazedarachin B (181) with a 1,2-hydrogen in 2-propanol led to acyl migration in ring A and gave its 1,2- shift.218 As for the structure of toosendanal (185), it contained diacetyl and 1,3-diacetyl isomers.193 Trichilin D (141) from one more lactol bridge at C-1/29 in addition to the C-19/29 Trichilia roka, first assigned in 1981,194 was subsequently ob- ether bridge.211 tained from Melia azedarach and mistaken for meliatoxin A1 in 2.1.5. Vilasinin-Class. The vilasinin-class limonoids charac- 1983.195 The structure of aphanastatin (142), along with amoor- terized by a 6α,28-ether bridge were proposed as biosynthetic astatin (165) and 12α-hydroxyamoorastatin (166) isolated from precursor of ring C cleaved salannin-type limonoids,237,238 which Aphanamixis grandifolia, has been determined from three-dimen- were formed through a Grob type olefin-forming fragmentation sional X-ray diffraction data.196,197 The absolute configuration of of a 12-hydroxy-14,15-epoxyvilasinin-class compound and sub- sendanin (156) was proposed based on CD data,198 and the sequent ether ring formation between C-7 and C-15 hydroxyl structure was confirmed by crystallographic means.199 As con- groups to yield nimbolidins and salannins.239 The occurrence of cerns biosynthesis, it should be noted that all trichilins isolated nimbolins A and B (202 and 366) in both Melia azedarach and from the root bark of Trichilia roka were oxidized at the C-2 Azadirachta indica further underlined the close relationship 194,200 240 positon, while 156 obtained from the fruit of T. roka was between the two species. Munronolide 21-O-β-D-glucopyranoside not oxidized at C-2.198 The structure of 156 could not be studied (213), from Munronia henryi, was the first limonoid with a 241 directly because it had been isolated from Melia azedarach only D-glucose moiety attached to the C-21 position. Malleastrones after acetylation of the crude limonoid fraction. Therefore the A-C (227 229) possessed a rare skeleton with an acetyl group at structure of its natural OH precursor was studied and it was C-6 and the C-6/29 ether bridge. Of these, the structure of 227 determined from the chemical and spectral data obtained that was confirmed by X-ray diffraction.242
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Table 3. Structures and Sources of Havanensin-Class Limonoids 106 134
no. compounds substitution groups and others sources
181 163 106 havanensin R1 =R2 =R3 =R4 =H Trichilia havanensis; Khaya anthotheca 163 74,181 107 3,7-di-O-acetylhavanensin R1 =R4 =H;R2 =R3 =Ac K. anthotheca; Trichilia havanensis 74,181 163 108 1,7-di-O-acetylhavanensin R1 =R3 = Ac; R2 =R4 =H T. havanensis; Khaya anthotheca 163 74,86,181 109 havanensin triacetate R1 =R2 =R3 = Ac; R4 =H K. anthotheca; Trichilia havanensis 182 110 trifolin R1 = Ac; R2 =H;R3 = iVal(OH); R4 =O T. trifolia 163,164,183 184 111 khayanthone R1 =R2 =R3 = Ac; R4 =O Khaya anthotheca; K. nyasica 164,178,185 112 grandifolione R1 =R2 = Ac; R3 =H;R4 =O K. grandifolia 113 1α-methoxy-1,2-dihydroepoxyazadiradione Azadirachta indica68 163 114 14,15-deoxyhavanensin 3,7-diacetate R1 =R4 =R5 =H;R2 =R3 =Ac Khaya anthotheca; Chisocheton paniculatus117 86 115 deoxyhavanensin triacetate R1 =R2 =R3 = Ac; R4 =R5 =H; Trichilia havanensis 86 186 116 14,15-deoxyhavanensin 1,7-diacetate R1 =R3 = Ac; R2 =R4 =R5 =H T. havanensis; Melia toosendan α α 90 117 1 ,12 -diacetoxy-7-deacetyl-1,2-dihydro- R1 = Ac; R4 = OAc; R2 =R3 =R5 =H Turraea cornucopia 3α-hydroxyazadirone 184 118 deoxykhayanthone R1 =R2 =R3 = Ac; R4 =H;R5 =O Khaya nyasica 86 119 R1 =R2 = Ac; R3 = OH; 20,22-didehydro Trichilia havanensis 187 120 melianin C R1 = Ac; R2 = Bz; R3 =H Melia volkensii 121 toosendone M. toosendan186 122 sendanal M. azedarach179 α α β α α fl 188 123 1 ,7 ,11 -triacetoxy-4 -carbomethoxy-12 - R1 =R3 = Ac; R2 =H;R4 = iBu Turraea oribunda (2-methylpropanoyloxy)-14β,15β-epoxyhavanensin α α β α α fl 188 124 1 ,7 ,11 -triacetoxy-4 -carbomethoxy-12 - R1 =R3 = Ac; R2 =H;R4 = Piv T. oribunda (2-methylbutanoyloxy)-14β,15β-epoxyhavanensin fl 189 125 R1 =R4 = Ac; R2 =R3 =H T. oribunda fl 189 126 R1 =R4 = Ac; R2 =H;R3 = iBu T. oribunda fl 189 127 R1 =H;R2 =R4 = Ac; R3 = iBu T. oribunda β α fl 190 128 11 -acetoxy-3,7-diacetyl-4 -carbomethoxy- R1 = Tig; R2 =R3 = Ac; R4 = iBu T. oribunda 12α-isobutyryloxy-28-nor-1-tigloyl-havanensin 191 129 nilotin R1 =R2 =R3 = Ac; R4 = Tig T. nilotica 130 1α,11β-diacetoxy-4α-carbomethoxy-7α- T. floribunda188 hydroxy-12α-(2-methylpropanoyloxy)-15-oxohavanensin α β fl 180 131 28-nor-4 -carbomethoxy-11 -acetoxy- R1 =R2 =Ac T. oribunda 12α-(2-methylbutanoyloxy)-14,15- deoxyhavanensin-1,7-diacetate α β fl 180 132 28-nor-4 -carbomethoxy-11 -hydroxy- R1 =R2 =H T. oribunda 12α-(2-methylbutanoyloxy)-14,15-deoxyhavanensin-1-acetate α β fl 180 133 28-nor-4 -carbomethoxy-11 -acetoxy- R1 =H;R2 =Ac T. oribunda 12α-(2-methylbutanoyloxy)-14,15-deoxyhavanensin-1-acetate 134 28-nor-4α-carbomethoxy-7-deoxy-7-oxo-11β-acetoxy- T. floribunda180 12α-(2-methylbutanoyloxy)-14,15-deoxyhavanensin-1-acetate
2.1.6. Others. The characterization of the epoxides 1α,2α- and F (66-68) and the complex compounds of the prieurianin- epoxy-17β-hydroxyazadiradione (248)and1α,2α-epoxyni- class.274 Kihadalactone A obtained from Aphanamixis polystacha molicinol (453)inAzadirachta indica oil was of biosynthetic in 1999275 was in fact identical with carapolide I (257) obtained significance, as they might be considered as intermediates from Carapa grandiflora in 1994.276 In addition, 257 was of between A-ring 3-oxo-Δ1,2 and 1,3-diols among the A. indica interest because the complex rohitukin limonoids could arise limonoids.115 from compounds of this relatively simple type by oxidation of ring B and the Δ14-double bond.275 2.2. Ring-seco Limonoids 2.2.1.2. Ring B-seco Group. Up to now, the limonoids of ring 2.2.1. Demolition of a Single Ring. 2.2.1.1. Ring A-seco B-seco (C-7/8) from Meliaceae were found only in the Turraea Group. The cleavage of C-3/4 and then formation of a 3,4- and Toona genera (Table 8). The substituents at C-11 in lactone mostly occurred in the ring A-seco group, and usually led turraflorins A C(266, 267, and 283), first isolated from Turraea to either the Δ1,2 system or 1α-acetyl substitution (Figure 9). floribunda,284 were revised to be β-oriented143 and the complete Dregeanas 3 5(256, 261, and 260) were considered as inter- assignment of the NMR spectra of 266 and 267 were presented.285 mediates between the intact limonoids such as heudelottins C, E, The structure of 6-acetoxytoonacilin (269), the first B-seco
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Figure 5. Structures of havanensin-class limonoids 106 134. limonoid with an intact A ring related to cedrelone (81), was methoxyazadirachtin (303) via selective bromomethoxylation confirmed by X-ray analysis.286 The absolute configurations of of the C-22,23 enol ether double bond and tri-n-butyltin hydride turrapubesins D G(275 278) were established by correlating reduction.305 A wonderful review of the chemistry of 292 was their CD spectra to that of turrapubesin B (1153),59 a model presented by Ley et al.,21 and a methodology of structure determi- compound whose absolute configuration was assigned by CD nation was also developed taking 292 as an example.306 The analysis of its dihydrogenated derivatives.266 Unlike the limo- structure of 3-tigloylazadirachtol (296),307 once incorrectly assigned noids 266 286, all of which have a Δ8,30 exocyclic double bond, as deacetylazadirachtinol,308 wasalsocalledazadirachtinB.309 turrapubesins A (290) and C (291) both have a Δ8,14 double Azaidrachtin F and 11-hydroxyazadirachtin B, both reported in 1996 bond, and the latter also has a 1,30-oxygen bridge. Wang et al. by two different research groups, had the same structure as presented the first report on the determination of the absolute 300.130,310 The spectral data of azadirachtin D (309), which was configuration of 290 by chlorine-based X-ray crystallography287 identical with 1-tigloyl-3-acetyl-11-hydroxy-4β-methylmeliacarpin and proposed a plausible biosynthetic pathway to 291 starting isolated in 1992,311 were introduced by Govindachari in the same from the precursor 11-epitoonacilin (271).126 year.312 Unlike most azadirachtin/meliacarpin-class limonoids, aza- 2.2.1.3. Ring C-seco Group. 2.2.1.3.1. Azadirachtin/Melia- dirachtin G (305) and 13,14-desepoxyazadirachtin A (306)hada carpin-Class. The ring C-seco limonoids originated mainly from double bond at C-13/14 instead of an epoxy moiety. 1,3-Diacetyl- the Azadirachta and Melia genera (Table 9). Deciphering the 11,19-deoxa-11-oxo-meliacarpin (311)fromAzadirachta indica was structure of the very potent biopesticide azadirachtin (292), first considered to be a possible intermediate in the biosynthesis of isolated from Azadirachta indica (syn. Melia azadirachta),51 also 292.313 called azadirachtin A according to Rembold,35 was a long 2.2.1.3.2. Azadirachtinin/Meliacarpinin-Class. It was thou- journey. Butterworth et al. presented the correct formula of ght that an intramolecular SN2 nucleophilic reaction resulted in 293 294 α β 292 as C35H44O16 and delineated important structural features. the formation of 7 ,13 -ether bridge moiety in azadirachtin/ Based on the NMR study including the NOE experiments, meliacarpin-class limonoids. 1-Cinnamoyl-3-acetyl-11-methoxy- the structure of 292 was proposed295,296 and subsequently meliacarpinin (327) reported in 1994339 was cited as meliacar- revised.297,298 The final and unambiguous determination did pinin A by Zhou et al. in 1997.214 It was odd that Nakatani et al. not arrive until 1986 based on the X-ray crystallographic analysis reported 1-deoxy-3-tigloyl-11-methoxymeliacarpinin (328)340 in of its derivatives,52,257 and thus reassignments of its NMR data 1993 and 1-acetyl-3-tigloyl-11-methoxymeliacarpinin (329)219 have been proposed by several research groups.299 301 Crystal- in 1994, but then presented these two compounds as meliacar- line 292 was obtained in 1994 and its crystal parameters were pins B and C in 1995,341 respectively. The structure 330 had been measured by X-ray diffraction.302,303 Then its absolute config- variously assigned to meliacarpinin D341 and, in 1995, to 1-tigloyl- uration was finally determined by high field NMR application of 3-acetyl-11-methoxymeliacarpinin,205 while 331 was reported the Mosher method.304 To determine the properties of 292,it as meliacarpinin E342 in 1996 and was in fact the 3-tigloyl-11- was converted to the natural product 22,23-dihydro-23β- methoxymeliacarpinin reported in 1993.206
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Table 4. Structures and Sources of Trichilin-Class Limonoids 135 185
no. compounds substitution groups and others sources
192 194 135 trichilin A R1 =R4 =H;R2 = OAc; Trichilia emetica; T. roka β R3 = Ac; R5 =O;R6 = -OH; R7 = Piv 200 136 7-acetyltrichilin A R1 =H;R2 = OAc; R3 =R4 = Ac; T. roka β R5 =O;R6 = -OH; R7 = Piv 194 137 trichilin B R1 =R4 =H;R2 = OAc; R3 = Ac; R5 =O; T. roka; Melia α 206,207,209,219,220 85,214 R6 = -OH; R7 = Piv azedarach; M. toosendan 206,207,209,219,220 214 138 12-O-acetyltrichilin B R1 =R4 =H;R2 = OAc; R3 = Ac; R5 =O; M. azedarach; M. toosendan α R6 = -OAc; R7 = Piv 206,207,209,219 221 139 1,12-diacetyltrichilin B R1 =R3 = Ac; R2 = OAc; R4 =H;R5 =O; M. azedarach α R6 = -OAc; R7 = Piv 194 140 trichilin C R1 =R4 =H;R2 = OAc; R3 = Ac; R5 = OH; Trichilia roka
R6=O;R7 = Piv 194 141 trichilin D (meliatoxin A1)R1 =R4 =R6 =H;R2 = OAc; R3 = Ac; T. roka; 195,206,207,209,219 222 R5 =O;R7 = Piv Melia azedarach 209,219 142 aphanastatin R1 =R3 = Ac; R2 = OH; R4 =H;R5 =O; M. azedarach; α fl 196 194 R6 = -OH; R7 = Piv Aphanamixis grandi ora; Trichilia roka 194,223 143 trichilin F R1 = Ac; R2 = OAc; R3 =R4 =H; R5 =O; T. roka β R6 = -OH; R7 = Piv 223 144 trichilin G R1 =R4 =H;R2 = OH; R3 = Ac; R5 =O; T. roka β R6 = -OH; R7 = Piv 206,207,209,219 221 145 trichilin H R1 =R4 =H;R2 = OAc; R3 = Ac; R5 =O; Melia azedarach; α 85,211,224 R6 = -OAc; R7 = iBu M. toosendan 221,225 85 146 1-acetyltrichilin H R1 =R3 = Ac; R2 = OAc; R4 =H;R5 =O; M. azedarach; M. toosendan α R6 = -OAc; R7 = iBu 221 147 1-acetyl-2-deacetyltrichilin H R1 =R3 = Ac; R2 = OH; R4 =H;R5 =O; M. azedarach α R6 = -OAc; R7 = iBu 221 148 3-deacetyltrichilin H R1 =R3 =R4 =H;R2 = OAc; R5 =O; M. azedarach α R6 = -OAc; R7 = iBu 221 149 1-acetyl-3-deacetyltrichilin H R1 = Ac; R2 = OAc; R3 =R4 =H;R5 =O; M. azedarach α R6 = -OAc; R7 = iBu 226 150 12-O-deacetyltrichilin H R1 =R4 =H;R2 = OAc; R3 = Ac; R5 =O; M. azedarach α R6 = -OH; R7 = iBu 85,209,224,227 151 trichilin I R1 =R4 =H;R2 = OH; R3 = Ac; R5 =O; M. toosendan α R6 = -OAc; R7 =Piv 221 152 12-deaceyltrichilin I R1 =R4 =H;R2 = OH; R3 = Ac; R5 =O; M. azedarach α R6 = -OH; R7 = Piv 85,209,224,227 153 trichilin J R1 =R4 =R6 =H;R2 = OH; R3 = Ac; M. toosendan
R5 =O;R7 = Piv 85,224 154 trichilin K R1 =R4 =R6 =H;R2 = OH; R3 = Ac; R5 =O; M. toosendan
R7 = iBu 85,224 155 trichilin L R1 =R3 =R4 =R6 =H;R2 = OAc; R5 =O; M. toosendan
R7 = Piv 199 198 156 sendanin R1 =R2 =R4 =H;R3 =R7 = Ac; R5 =O; M. azedarach; Trichilia roka α R6 = -OAc; 205 202 204 157 29-deacetylsendanin R1 =R2 =R4 =R7 =H;R3 = Ac; R5 =O; Melia azedarach; M. toosendan α R6 = -OAc; α 206,207,209,219 85,224 158 azedarachin A R1 =R2 =R4 =H;R3 = Ac; R5 =O;R6 = -OH; M. azedarach; M. toosendan
R7 = Piv 205,207,209,219 85,133 159 12-O-acetylazedarachin A R1 =R2 =R4 =H;R3 = Ac; R5 =O; M. azedarach; M. toosendan α R6 = -OAc; R7 = Piv 205,206,218 85,214 160 azedarachin B R1 =R2 =R4 =H;R3 = Ac; R5 =O; M. azedarach; M. toosendan α R6 = -OH; R7 = iBu 207,209,219 224 161 12-O-acetylazedarachin B R1 =R2 =R4 =H;R3 = Ac; M. azedarach; M. toosendan α (29-isobutylsendanin) R5 =O;R6 = -OAc; R7 = iBu
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Table 4. Continued no. compounds substitution groups and others sources 206,209,228 162 azedarachin C R1 =R2 =R4 =R6 =H;R3 = Ac; M. azedarach
R5 =O;R7 = iBu 195,206,207,219,220,222 163 meliatoxin A2 R1 =R4 =R6 =H;R2 = OAc; R3 = Ac; M. azedarach
R5 =O;R7 = iBu 208 164 meliartenin R1 =R2 =R4 =R7 =H;R3 = Ac; R5 = OH; M. azedarach
R6 =O 217 165 amoorastatin R1 =R2 =R4 =R6 =R7 =H;R3 = Ac; Pterohrachis zenkeri; fl 229 R5 =O Aphanamixis grandi ora α fl 210 85,133,214 166 12 -hydroxyamoorastatin R1 =R2 =R4 =R7 =H;R3 = Ac; R5 =O; A. grandi ora; Melia toosendan; α 201,205,209,213,230 (12-deacetyltoosendanin) R6 = -OH M. azedarach 85,133,211,212,214 167 chuanliansu (toosendanin; R1 =R2 =R4 =R7 =H;R3 = Ac; R5 =O; M. toosendan; α α 209,213,230 12 -acetoxyamoorastatin) R6 = -OAc M. azedarach α 217 168 3 -deacetylamoorastatin R1 =R2 =R3 =R4 =R6 = Pterohrachis zenkeri
R7 =H;R5 =O β 217 169 9 -amoorastatin R1 =R2 =R4 =R6 =R7 =H;R3 = Ac; P. zenkeri β R5 =O;9 -H α 133 170 meliatoosenin D R1 =R2 =R3 =R4 =H;R5 =OR6 = -OAc; Melia toosendan
R7 =OH 171 meliatoosenin C M. toosendan133 α fl 210 230 172 amoorastatone R1 = -OH; R2 =R4 =R5 =H; Aphanamixis grandi ora; Melia azedarach α R3 = -OAc α α α 213,230 232 85,133,225 173 12 -hydroxyamoorastatone R1 = -OH; R2 =R5 =H;R3 = -OAc; M. azedarach; M. toosendan
R4 =OH α α α 233 174 29-[(2-methylbutanoyl)oxy]-2 - R1 = -OH; R2 = OH; R3 = -OAc; M. toosendan
hydroxyamoorastatone R4 =H;R5 = Piv α β β 233 175 1,3-epi-29-[(2-methylbutanoyl)oxy]-2 - R1 = -OH; R2 = OH; R3 = -OAc; R4 =H; M. toosendan
hydroxyamoorastatone R5 = Piv α β β 233 176 1,3-epi-29-[(2-methylpropanoyl)oxy]-2 - R1 = -OH; R2 = OH; R3 = -OAc; R4 =H; M. toosendan
hydroxyamoorastatone R5 = iBu α α 195,211,221,222 177 meliatoxin B1 R1 = -OH; R2 = OAc; R3 = -OAc; R4 =H; M. azedarach
R5 = Piv α α 195,222 178 meliatoxin B2 R1 = -OH; R2 = OAc; R3 = -OAc; R4 =H; M. azedarach
R5 = iBu α α 230,234 85,225,234,235 179 isochuanliansu (isotoosendanin) R1 = -OH; R2 =R5 =H;R3 = -OAc; M. azedarach; M. toosendan
R4 = OAc α α 85,225 180 neoazedarachin A R1 = -OH; R2 =H;R3 = -OAc; R4 = OH; M. toosendan
R5 = Piv α α 85,218,225 181 neoazedarachin B R1 = -OH; R2 =H;R3 = -OAc; R4 = OH; M. toosendan
R5 = iBu α α 225 182 neoazedarachin D R1 = -OH; R2 =H;R3 = -OAc; R4 = OH; M. toosendan
R5 =CH3 183 7,14-epoxyazedarachin B M. azedarach218 184 azadirachtanin Azadirachta indica236 185 toosendanal Melia toosendan211
2.2.1.3.3. Salannin-Class. The structures of salannin (332) The molecules of 20,30-dehydrosalannol (338) were linked into and 3-deacetylsalannin (333), in which many of the conforma- chains by intermolecular O H 333O hydrogen bonds.349 The 14 3 tions were similar to those of in azadirachtins, were confirmed by biosynthetic pathway to nimbolide (345)from[2- C,(4R)4- H1]- X-ray diffraction analysis.347 Photooxidation of 332 and nimbin mevalonic acid lactone was confirmed by feeding expe- (391) by UV light in the presence of oxygen led to more polar riments.350 354 The isomer of 345 was unexpectedly produced unstable intermediates that rearranged on silica gel to two final when it was treated with boron trifluoride etherate and tetrabutyl products in which the furan ring had been oxidized to isomeric ammonium bromide.355 Salannolide356 and compositolide253 hydroxybutenolides.348 The photooxidation products of 332, were both obtained in 1984 by two research groups, and had salanninolide (349), and its isomer isosalanninolide (348)were the same structure as 348. In addition, it was mistaken for also isolated as natural products from Azadirachta indica.317,318 isosalanninolide by Jarvis et al. in 1999.317
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Figure 6. Structures of trichilin-class limonoids 135 185.
2.2.1.3.4. Nimbolinin-Class. It seems that melianolide (389) data415 presented were used for its characterization, and its was situated in a position to link ring C-seco limonoids such as constitution and relative stereochemistry were deduced from nimbolinin B (358) to azadirachtinin-class limonoids.361 The the dihydrogedun-3β-yl iodoacetate416 derivative and confirmed biosynthetic routes from ohchinolide A (371) to salannal (396) by X-ray diffraction analysis.417 Moreover, reactions of 416 were and further to salannin (332) involving Grob type olefin forma- described and explained by a structure similar to that proved for tion and subsequent ether ring formation were presented.361 limonin.418 The crystal structure of 6α-acetoxygedunin (418) Zhang et al. proposed 12-ethoxynimbolinins A D186 for the was determined by X-ray analysis.419 The 1H NMR data of structure of 357, 361, 385, and 388 based on comparison of the 7-deacetylgedunin (421) had not been completely assigned until skeleton with the virtual compound nimbonlinin, which was a 2006113 although it was isolated from Azadirachta indica in presumed intermediate in the biosynthetic pathway to more 1967.57 Cespedes et al. presented the isolation of the epimeric highly rearranged limonoids not yet isolated as a natural product. mixture of photogedunin (433) and the formation and phyto- However, 12-ethoxynimbolinins A D were not simple ethoxyl synthetic activities of its acetates.420 The chemical conversion of derivatives of nimbolinin A D(355, 358, 363, and 364), which 416 and khivorin (434) to deacetoxy-7-oxoisogedunin con- might cause misunderstanding and confusion.212 firmed the structure of 434.421 The crystal packing of 3α,7α- 2.2.1.3.5. Nimbin-Class. The structure of nimbin (391), the dideacetylkhirorin (440) was stabilized by both intra- and major crystal bitter constituent of Azadirachta indica, was char- intermolecular hydrogen bonds, whose six-membered rings acterized by chemical means392 401 and spectroscopic ana- showed chair, boat and half-chair conformations while the furan lysis.402 The assignment of the absolute configuration in 391 ring was planar.422 Biosynthetically, formation of mahmoodin was determined by making certain biosynthetic assumptions403 (454), the first limonoid with a C-17 ethylene glycol side chain, and using information from the ORD study of pyronimbic acid.404 might be considered as being from isonimolicinolide (59) The NMR spetral data of 391,6-deacetylnimbin(392), nimbanal through oxidation of ring D to a δ-lactone, as is observed in (393), and nimbolide (345) were subsequently partially reassigned the case of the epoxyazadiradione-gedunin conversion, followed in 1990.377 Ohchinolal (396), obtained from Melia azedarach early by transformation of the acetyl group to an ethylene glycol in 1983,370 was isolated from the same species and renamed as group.81 salannal by Nakatani et al. in 1995.360 3-O-Acetylohchinolal (399) 2.2.2. Demolition of Two Rings. 2.2.2.1. Rings A,B-seco was considered to be one of the biosynthetic precursors to the ring Group. 2.2.2.1.1. Prieurianin-Class. The complex prieurianin- C-seco limonoids with C-6/28 and C-7/15 ether linkages, such as class limonoids were depicted as arising from cleavages of C-3/4 are found in salannin (332) and ohchinin (340).84 and C-7/8 and the formation of 3(4)-lactone or 7(4)-lactone, 2.2.1.3.6. Nimbolidin-Class. Walsogyne (414), with a C-11/14 with the substitution of a formyloxy or acetoxy group at C-11 ether bridge, might be derived through keto enol isomerization of (Figure 18 and Table 16). Prieurianin (458), first isolated from the aldehyde at C-9 followed by formation of a tetrahydrofuran-2- Trichilia prieuriana, is the representative compound of this ol.412 7α-Acetyl-15β-methoxy-29-methylene-7,15-deoxonimbolide class,168 but the presence of multiple conformational isomers (415)shouldbenamedas7α-acetyl-15β-methoxy-28a-methylene- at room temperature caused its 1H NMR peaks to be poorly 7,15-deoxonimbolide based on its skeleton numbering, and the resolved so that its structure remained obscure. However, the 1H source of C-28a was not biosynthetically available.411 NMR spectrum was well resolved when the sample was heated 2.2.1.4. Ring D-seco Group. Limonoids in this group with a to ∼67 °C so that at that temperature it was possible to perform a δ-lactone in ring D derived from azadirone class via ring expansion detailed analysis and make proton assignments.481 Similarly, its by a Baeyer Villiger type reaction.413 Gedunin (416), the 13C NMR spectrum should be measured at 50 °C to avoid broad representative compound of this class, was obtained from various or missing peaks which occur in measurements made at 33 °C. species (Table 15). For 416 the MS135,414 and NMR spectral Finally, the structure of 458 was unambiguously confirmed
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Table 5. Structures and Sources of Vilasinin-Class Limonoids 186 229
no. compounds substitution groups and others sources
238 186 vilasinin R1 =R2 =R3 =R4 =H Azadirachta indica α α fi 188 243 187 1 -acetyl-3 -propionylvilasinin R1 = Ac; R2 = propanoyl; R3 =R4 =H Turraea wake eldii; T. parvifolia α α α 243 188 1 ,3 -diacety-7 -tigloylvilasinin R1 =R2 = Ac; R3 = Tig; R4 =H T. parvifolia α α 243 143 189 1 ,3 -diacetylvilasinin R1 =R2 = Ac; R3 =R4 =H T. parvifolia; T. holstii; Chisocheton paniculatus;117 Malleastrum antsingyense;244 Melia volkensii;187 Azadirachta indica245 α 130 244 190 1,3-diacetyl-7-tigloyl-12 - R1 =R2 = Ac; R3 = Tig; R4 =OH A. indica; Malleaxtrum antsingyense hydroxyvilasinin 237 191 trichilinin R1 =R3 =H;R2 = Ac; R4 = OAc Trichilia roka 246 186,212 192 1-cinnamoyltrichilinin R1 = Cin; R2 = Ac; R3 =H;R4 = OAc Melia volkensii; M. toosendan 246 193 1-tigloyltrichilinin R1 = Tig; R2 = Ac; R3 =H;R4 = OAc M. volkensii 246 186 194 1-acetyltrichilinin R1 =R2 = Ac; R3 =H;R4 = OAc M. volkensii; M. toosendan 85,186,239 195 trichilinin B R1 = Tig; R2 = Ac; R3 =H;R4 = OAc M. toosendan 85,239 196 trichilinin C R1 = Ac; R2 = Tig; R3 =R4 =H M. toosendan 85,212,247 197 trichilinin D R1 = Cin; R2 =R3 =H;R4 = OAc M. toosendan 85,212,247 198 trichilinin E R1 = Bz; R2 =R3 =H;R4 = OAc M. toosendan 187 199 meliavolkinin R1 = Bz; R2 = Ac; R3 =R4 =H M. volkensii 248 200 meliavolkin R1 = Cin; R2 = Ac; R3 =R4 =H M. volkensii 249,250 201 nimbidinin R1 =R2 =R3 =H;R4 =O Azadirachta indica 240 240,251 202 nimbolin A R1 =R2 = Ac; R3 = Cin; R4 =H A. indica; Melia azedarach; M. birmanica252 253 203 compositin R1 =R3 = Tig; R2 =R4 =H M. dubia 254 204 compositin acetate R1 =R3 = Tig; R2 = OAc; R4 =H M. composita 255 205 dysoxylin A R1 = Ac; R2 =R5 =H;R3 = Tig; R4 = OAc; Dysoxylum gaudichaudianum
R6 = O; 20,22-dihydro 255 206 dysoxylin B R1 = Ac; R2 =R5 =H;R3 = Bz; R4 = OAc; D. gaudichaudianum
R6 = O; 20,22-dihydro 255 207 dysoxylin C R1 = Ac; R2 =R5 =H;R3 = Piv; R4 = OAc; D. gaudichaudianum
R6 = O; 20,22-dihydro 255 208 dysoxylin D R1 = Ac; R2 =R5 =H;R3 = 3,4-dimethylpent-2-enoyl; D. gaudichaudianum
R4 = OAc; R6 = O; 20,22-dihydro 256 209 azadirachtolide R1 = Sen; R2 = Ac; R3 =R4 =R5 =H;R6 =O Azadirachta indica 256 210 deoxyazadirachtolide R1 = Sen; R2 = Ac; R3 =R4 =R5 =R6 =H A. indica 70,257 211 3-acetoxy-7-tigloylvilasinin lactone R1 =R4 =R5 =H;R2 = Ac; R3 = Tig; R6 =O A. indica Δ20,22 241 212 munronolide R1 =R2 = Ac; R3 =R4 =H;R5 = OH; R6 =O; Munronia henryi β β Δ20,22 241 213 munronolide 21-O- -D- R1 =R2 = Ac; R3 =R4 =H;R5 = -D-glc; R6 =O; M. henryi glucopyranoside 258 214 neem A R1 =R2 =R3 =R4 =R5 =H;R6 =O Azadirachta indica 258 215 neem B R1 =R2 =R3 =R4 =R5 =R6 =H A. indica 216 munronin G Munronia delavayi259 260 217 limbocinin R1 =R2 =H Azadirachta indica 260 218 limbocidin R1 =R2 =OH A. indica β β β β 261 219 TS1 R1 = OH; R2 =H;9 ,11 -epoxy; 14 ,15 -epoxy Trichilia rubescens β β 261 220 TS2 R1 = OCOC(CH3)=CH2;R2 =H;9 ,11 -epoxy; T. rubescens 14β,15β-epoxy β β β β Δ6,7 261 221 TS3 R1 =R2 =H;9 ,11 -epoxy; 14 ,15 -epoxy; T. rubescens Δ14,15 262 222 ceramicine B R1 =R2 =H; Chisocheton cermicus Δ14,15 262 223 ceramicine C R1 =H;R2 = methylacryl; C. cermicus 262 224 ceramicine D R1 =R2 =H C. cermicus β β 263 225 trichirubine B R1 = OBz; R2 = OH; 9 ,11 -epoxy Trichilia rubescens 226 trichirubine A T. rubescens263 Δ1,2 242 227 malleastrone A R1 =H;R2 =CH3; a Malleastrum sp. Δ1,2 242 228 malleastrone B R1 =H;R2 =CH2CH3; a Malleastrum sp. 242 229 malleastrone C R1 = OH; R2 =CH3 a Malleastrum sp.
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Figure 7. Structures of vilasinin-class limonoids 186 229.
Table 6. Other Structures and Sources of Rings Intact Limonoids 230 248
no. compounds substitution groups sources
230 neeflone Azadirachta indica264 231 Cedrela odorata265 β α α β fl 143 232 11 -acetoxy-7 -acetyl-12 -hydroxy-1,2-dihydroneotrichilenone R1 = Ac, R2 = -OAc; R3 =OH Turraea oribunda α fl 143 233 12 -acetoxy-7-acetyl-1,2-dihydroneotrichilenone R1 = Ac, R2 =H;R3 = OAc T. oribunda α fl 143 234 12 -acetoxy-1,2-dihydroneotrichilenone R1 =R2 =H;R3 = OAc T. oribunda 235 turranolide R = H T. robusta87 236 lenticellatumin R = OH Dysoxylum lenticellatum266 87 237 1,2-dihydroazadirone R1 =O;R2 =R4 =H;R3 =Ac Turraea robusta α 243 238 12 -acetoxy-1,2-dihydroazadirone R1 =O;R2 =H;R3 = Ac; R4 = OAc T. parvifolia α 267 239 1,2-dihydro-6 -acetoxyazadirone R1 =O;R2 = OAc; R3 = Ac; R4 =H Chisocheton paniculatus 87,268 243 240 mzikonone R1 =O;R2 =R3 =H;R4 = OAc Turraea robusta; T. parvifolia; T. cornucopia90 87 241 mzikonol R1 = OH; R2 =R3 =H;R4 = OAc T. robusta 269 242 meldenindiol R1 =O;R2 = OH; R3 =R4 =H Azadirachta indica 134,270,271 176 243 meldenin R1 = Ac; R2 =H A. indica; Melia azedarach 62,92,270,271 244 isomeldenin R1 =H;R2 =Ac Azadirachta indica 245 meliatetraolenone A. indica272 246 1β,2β;21,23-diepoxy-7α-hydroxy-24,25,26,27- Trichilia havanensis273 tetranor-apotirucalla-14,20,22-trien-3-one 247 1β,2β-diepoxyazadiradione Azadirachta indica68 248 1α,2α-epoxy-17β-hydroxyazadiradione A. indica115 by X-ray analysis of prieurianin 20-p-bromobenzenesulpho- subsequently reassigned for the formate, acetyl, methylene nate,481,482 and the stereochemical ambiguities remaining for groups and for two quaternary carbons.485 X-ray crystallography C-1, C-4 and C-14 were resolved.481 Just as for 458, spectral showed that rohituka 7 (483) bore the 15β-substituent,486 as measurements of epoxyprieurianin (464),454 dysoxylumins A-C opposed to the original assignment.484 The assigned structure of (465 467),483 androhitukas1,2,4,and7 9(490, 491, 459, 483, dregeanin with ring A as a seven-membered lactone487 was 469,and484)484 were performed at 60 °C to obviate the difficulties revised by comparison of the spectroscopy data with those of caused by restricted rotation around the C-9/10 bond at lower prieurianin derivatives to contain instead an eight-membered temperatures. The isolation of these compounds was impeded, just lactone ring as is shown in 488.488 Cipadessalide (489), the first as was previously experienced for rohitukas and prieurianin, by prieurianin-class compound isolated from Cipadessa plants, was difficulties such as a mild alkaline hydrolysis causing opening of the the first example of a limonoid with an oxygen bridge between ring A-lactone, followed by a variety of further changes, which C-1 and C-30. Moreover, a biosynthetic relationship between 489 produced a complex mixture of products difficult to resolve.484 and mombasol (471) was proposed.282 MacLachlan et al. revised Some complicated prieurianin-class structures were revised the seven membered 3(4)-lactone ring in rohitukas 1, 2 (490, with the development of new structure determination tech- 491)484 and D-5 (493)489 as five membered 7(4)-lactone rings and niques. The 13C NMR data of Tr-B (479)wereanalyzed192 and expressed doubt as to whether they were true natural products.490
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Figure 8. Other structures of rings intact limonoids 230 248.
Figure 9. Structures of ring A-seco limonoids 249 265.
2.2.2.1.2. Others. All of 494 497 contain 3-oxo-Δ1,2 system the previously reported assignment275 of the ester carbons (C-10, and 3(4)-lactone groups, with toonaciliatin E and H (494 C-3) and quaternary carbons (C-10, C-14) was presented.485 and 495) having an 8α,14α-epoxide, while toonaciliatin I Limonoids 514 517 are characterized by the 1α,14β-ether (496) and surenolactone (497) have a 14β,15β-epoxide bridge. linkage, Δ8,30 system and 15-oxo groups. Although previously The co-occurrence of 494 496 in Toona ciliata suggested that reported differently,503 the C-1 substituent in polystachin (517) 494 and 495 might derive from 496 through an acid-catalyzed has been reassigned as α.275 Rubrins A-G (518 524), isolated intramolecular rearrangement followed by an oxidation and from Trichilia rubra in 1994, possessed the C-3/29 cyclic hemi acetylation of 495 to produce 494.290 Zhang et al. demonstrated ortho ester structure, which alleviated the steric congestion of that the 13C NMR data previously reported for rohituka 3 groups in the vicinity of the C-9, C-10 bond and thus eliminated (507)192 agreed instead with the structure for rohituka 15 the broadening of their 1H NMR peaks.504 Among them, the (516).485 For rohituka 14 (510) a complete reassignment of structures of rubrins C and E (520 and 522) were identical to
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Table 7. Structures and Sources of Ring A-seco Limonoids 249 265
no. compounds substitution groups and others sources 277 fl 276 249 evodulone R1 =H,R2 = OAc; R3 =O Carapa procera; C. grandi ora 278 250 surenin R1 =R2 = OAc, R3 =H Toona sureni 278 251 surenone R1 = OH; R2 =O,R3 =H T. sureni 252 carapolide H Carapa grandiflora276 253 amotsangin G Amoora tsangii279 254 proceranone Carapa procera280 281 255 rubralin C R1 =H;R2 = Tig, R3 = OAc Trichilia rubra 274 256 dregeana 3 R1 =H;R2 = Ac, R3 = O-(2-acetoxy-3-methylpentanoxy) T. dregeana fl 276 275 257 carapolide I (kihadalactone A) R1 =R3 =H;R2 =Ac Carapa grandi ora; Aphanamixis ploystacha 75 258 delevoyin B R1 = OAc; R2 = Ac; R3 =H Entandrophragma delevoyi 99 259 quivisianthone R1 = OH; R2 = Ang; R3 =H Quivisia papinae 274 260 dregeana 5 R1 = iVal(OH); R2 = 2-acetoxypivaloyl Trichilia dregeana β 274 192 261 dregeana 4 R1 = iBu(OH); R2 = -O-(2-acetoxypivaloyl); R3=H T. dregeana; T. emetica α 281 262 rubralin A R1 =R3 = 2-hydroxy-3-methylpentanoyl; R2 = -OAc T. rubra α 281 263 rubralin B R1 = iVal(OH); R2 = -OAc; R3 = 2-hydroxy-3-methylpentanoyl T. rubra α 282 264 rubralin D R1 = iVal(OH); R2 = -OAc; R3 = 2,3-dihydroxy-3-methylvaleroyl Cipadessa baccifera 265 nymania 2 Nymania capensis283
Table 8. Structures and Sources of Ring B-seco Limonoids 266 291
no. compounds substitution groups and others sources
266 turraflorin A R = Ac Turraea floribunda284,285 267 turraflorin B R = H T. floribunda284,285 α 140,161,286,288,289 268 toonacilin R1 =H;R2 = -OAc; R3 = OAc Toona ciliata α 286,288,289 269 6-acetoxytoonacilin R1 =R3 = OAc; R2 = -OAc T. ciliata α 140 270 12-deacetoxytoonacilin R1 =R3 =H;R2 = -OAc T. ciliata β fl 143 271 11-epi-toonacilin R1 =H;R2 = -OAc; R3 = OAc Turraea oribunda fl fl 285 272 turra orin D R1 = Ac; R2 =O;R3 =OH T. oribunda fl fl 285 126 273 turra orin E R1 = Ac; R2 = OH; R3 =O T. oribunda; T. pubescens fl fl 285 274 turra orin F R1 =R3 =H;R2 =O T. oribunda β 126 275 turrapubesin D R1 = -OAc; R2 = COCH2Ph; R3 =O;R4 =OH T. pubescens β 126 276 turrapubesin E R1 = -OAc; R2 = COCH2Ph; R3 = OH; R4 =O T. pubescens β 126 277 turrapubesin F R1 = -OAc; R2 = iBu; R3 = OH; R4 =O T. pubescens β 126 278 turrapubesin G R1 = -OAc; R2 = Piv; R3 = OH; R4 =O T. pubescens α 288,289 279 21-(R,S)-hydroxytoonacilide R1 = -OAc; R2 = Ac; R3 = OH; R4 =O Toona ciliata α 154,288,289 280 23-(R,S)-hydroxytoonacilide R1 = -OAc; R2 = Ac; R3 =O;R4 =OH T. ciliata β 125 281 11-epi-21-hydroxytoonacilide R1 = -OAc; R2 = Ac; R3 = OH; R4 =O Turraea parvifolia β 125 282 11-epi-23-hydroxytoonacilide R1 = -OAc; R2 = Ac; R3 =O;R4 =OH T. parvifolia fl fl 284 283 turra orin C R1 = Ac; R2 = OAc T. oribunda fl fl 285 284 turra orin H R1 =R2 =H T. oribunda 285 turraflorin I T. floribunda285 286 turraflorin G T. floribunda285 287 toonaciliatin B Toona ciliata290 288 toonaciliatin C T. ciliata290,291 289 toonafolin T. ciliata292 290 turrapubesin A Turraea pubescens287 291 turrapubesin C T. pubescens126 those of hispidin A isolated from T. hispida in 1981501 and 2.2.2.2. Rings A,D-seco Group. Rings A,D-seco limonoids nymania 1 isolated from T. emetica in 1998,192 respectively. found in Meliaceae, most of which belong to the obacunol-class, Unlike the rohitukas 6, 3, 5, 13, 14 (505, 507 510), 511, were found only in the Toona, Cedrela, and Dysoxylum genera dysoxylumolide A (512), and dysoxylumic acid (506), toonaci- (Table 18). Except for dysoxylumolide C (554) and odoralide liatin D (513) was deduced on the basis of its NOESY spectrum (555), they were characterized by a 3(4)-lactone with an to have 1β-substituent.290 epoxidized δ-lactonic D ring.510 The biosynthesis of the
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Figure 10. Structures of ring B-seco limonoids 266 291. limonoids with an epoxy-lactone ring D proceeded through a peroxide oxidation of a 7-oxo compound or an earlier intermediate 14,15-unsaturated meliacane, which was successively oxidized to in the biosynthesis.530 The unusual chemical shift of the acetate δ α a 14(15)-en-16-one, to a 14,15-epoxy-16-one, and finally to the methyl group ( H 1.55) in methyl 6,12 -diacetoxyangolensate lactone.77 The structures of the three limonoids 11-oxo-7α- (571) was caused by the shielding effect of the furan ring.531 Both obacunol (532), 11-oxo-7α-obacunyl acetate (533), and 11- sandoricin (573) and its 6-hydroxy derivative 574 were determined oxocneorin G (548), all of which contain the rare 11-ketone by NMR, mass spectra, and X-ray analysis.532 It is worth noting that functionality, were confirmed by X-ray analysis.511 Of the seven the two compounds 57853 and 103854 were reported separately by kihadanin A and B derivatives obtained from Trichilia elegans ssp. two research groups in 2007, and both compounds were named as elegans, the structure of 7-deoxo-7α-acetoxykihadanin A (539) cipadesin D, but different skeletons were ascribed to them. was confirmed by X-ray crystallographic analysis.512 7-Deoxo-7α- 2.2.2.3.2. Others. Secomahoganin (596), in which ring C had hydroxykihadanin A (538) and 7-deoxo-7β-hydroxykihadanins A a skew-boat conformation, was formed by oxidative cleavage of and B (540 and 544) were isolated after acetylation procedures as the C-6/7 bond in the normal tetranortriterpene nucleus and was their mono- and/or diacetate derivatives.512 Moreover, limonoids an interesting compound from a biosynthetic viewpoint.71 540 and 544, together with 7-deoxo-7β-acetoxykihadanins A and Cedrelanolide I (599), for which the structure was established B(541 and 545), were the first reported natural occurrence of by spectroscopic methods and X-ray diffraction analysis, might C-7β-substituted limonoids without any oxygenated function at be biosynthetically derived from a methyl angolensate type of C-6.512 Ng et al. reported the crystal structure of 7α-acetoxydihy- precursor.570 However, Cespedes et al. cited it as cedrel- dronomilin (546)513 and subsequently pointed out that it origi- anolide.571 The structure of swiemahogin A (600), confirmed nated from Xylocarpus granatum rather than Uncaria gambier.514 by single-crystal X-ray diffraction, incorporated a rare five- 2.2.2.3. Rings B,D-seco Group. 2.2.2.3.1. Andirobin-Class. membered γ-lactone fused to the C-ring at C-8 and C-14, where Andirobin-class limonoids are characterized as the cleavages of the six-membered δ-lactone in the D-ring was destroyed.572 C-7/8 and C-16/17 and the formation of Δ8,30 exocyclic double 2.2.3. Demolition of Three Rings (Rings A,B,D-seco bond and δ-lactonic D ring. The chemical correlations of Group). Methyl ivorensate (601), the first A,B,D-seco limonoid gedunin (416) with 556 and with methyl angolensate (568) obtained from plants of family Meliaceae, was structurally related supported the structures previously proposed for 556 and 568.523 to methyl angolensate (568) since treatment of 568 with Methyl angolensate (568) was distributed widely, especially in perbenzoic acid produced a moderate yield of the corresponding the genus Khaya (Table 19). Its structure was proposed on the lactone 601.576 A detailed analysis of the NMR data of 601 was basis of chemical and spectroscopic evidence524 526 and con- presented but some assignments were interchanged.446 firmed by X-ray crystallographic analysis.527 The partial synthesis of 568 from 7-deacetoxy-7-oxokhivorin (441) has proved that 2.3. Rearranged Limonoids the configuration of the etheroxygen attached to C-1 was 2.3.1. 1,n-Linkage Group. It is interesting that the carapo- α.528,529 Compound 568 might arise by a Bayer Villiger type lide-class compounds 607 613 were found only in genus
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Table 9. Structures and Sources of Azadirachtin/Meliacarpin Limonoids 292 315
no. compounds substitution groups and others sources
314 51,293,295,300,315 321 292 azadirachtin (azadirachtin A) R1 = Tig; R2 = Ac; R3 =OH Melia azedarach; Azadirachta indica; A. excelsa322 257 293 3-deacetyl-11-desoxyazadirachtin R1 = Tig; R2 =R3 =H A. indica 300 294 3-deacetyl-3-cinnamoylazadirachtin R1 = Tig; R2 = Cin; R3 =OH A. indica 323 324 295 azadirachtol R1 =R2 =R3 =H A. indica; A. excelsa 70,300,309,316,317,319,325,326 324 296 3-tigloylazadirachtol (azadirachtin B, R1 =R3 =H;R2 = Tig A. indica; A. excelsa deacetylazadirachtinol) 322 327 297 1-tigloyl-3-acetylazadirachtol R1 = Tig; R2 = Ac; R3 =H A. excelsa; A. siamensis α α 328 298 3 -acetoxy-1 -hydroxyazadirachtol R1 =R3 =H;R2 =Ac A. indica 35 299 azadirachtin E R1 =H;R2 = Ac; R3 =OH A. indica 130,310 300 azadirachtin F (11-hydroxyazadirachtin B) R1 =H;R2 = Tig; R3 =OH A. indica 324 301 azadirachtin O R1 = iVal; R2 = Ac; R3 =H A. excelsa 324 302 azadirachtin Q R1 =R2 = Ac; R3 =H A. excelsa β β 70,298,300,325 303 22,23-dihydro-23 -methoxyazadirachtin (vepaol) R = -OCH3 A. indica α 70,325 304 isovepaol(23-epi-vepaol) R = -OCH3 A. indica 305 azadirachtin G A. indica35 306 13,14-desepoxyazadirachtin A A. indica329 307 azadirachtin K A. indica102 308 1-cinnamoylmelianolone Melia azedarach330 332 β 311,317,319,333,334 309 azadirachtin D (1-tigloyl-3-acetyl-11-hydroxy-4 - R1 = OH; R2 = COOCH3 Azadirachta indica methylmeliacarpin) 70,335 310 11-epi-azadirachtin D R1 = COOCH3;R2 =OH A. indica 311 1,3,-diacetyl-11,19-deoxa-11-oxomeliacarpin A. indica313 312 1-cinnamoyl-3,11-dihydroxymeliacarpin R = H Melia azedarach331,336,337 313 1,3-dicinnamoyl-11-hydroxymeliacarpin R = Cin M. azedarach338 314 1-cinnamoyl-3-acetyl-11-hydroxymeliacarpin R = Ac M. azedarach338 315 1-cinnamoyl-3-methacrylyl-11-hydroxymeliacarpin R = methacrylyl M. azedarach338
Figure 11. Structures of azadirachtin/meliacarpin-class limonoids 292 315. carapa, the dukunolide-class limonoids 614 620 originated in came from genus Turraea (Table 22). A possible biosynthetic genus Lansium, the neotecleanin-class compounds 621 625 pathway leading to the carapolides from carapolide G (613)as
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Table 10. Structures and Sources of Azadiracthinin/Meliacarpinin Limonoids 316 331
no. compounds substitution groups and others sources
325 316 3-tigloylazadiracthinin R1 =R3 =H;R2 = Tig Azadirachta indica 130,325 317 1-tigloyl-3-acetylazadirachtinin R1 = Tig; R2 = Ac; R3 =H A. indica 70,300 318 1-tigloyl-3-acetyl-11-methoxyazadirachtinin R1 = Tig; R2 = Ac; R3 =CH3 A. indica 319 azadirachtin N A. indica343 344 320 3,20-diacetyl-11-methoxymeliacarpinin R1 =H;R2 =R3 =Ac Melia azedarach 345 133 321 1-tigloyl-3,20-diacetyl-11-methoxymeliacarpinin R1 = OTig; R2 =R3 =Ac M. azedarach; M. toosendan 345 133 322 3-tigloyl-1,20-diacetyl-11-methoxymeliacarpinin R1 = OAc; R2 = Tig; R3 =Ac M. azedarach; M. toosendan 345 323 1-cinnamoyl-3-hydroxy-11-methoxymeliacarpinin R1 = OCin; R2 =R3 =H M. azedarach 345 324 1-deoxy-3-methacrylyl-11-methoxymeliacarpinin R1 =R3 =H;R2 = methacrylyl M. azedarach 346 325 1-(2-methylpropanoyl)-3-acetyl-11-methoxymeliacarpinin R1 = OiBu; R2 = Ac; R3 =H M. azedarach 346 326 1-methacrylyl-3-acetyl-11-methoxymeliacrpinin R1 = methacrylate; R2 = Ac; R3 =H M. azedarach 206,209,339,345 85,133,214 327 1-cinnamoyl-3-acetyl-11-methoxymeliacarpinin (meliacarpinin A) R1 = OCin; R2 = Ac; R3 =H M. azedarach; M. toosendan 209,219,340,341 328 1-deoxy-3-tigloyl-11-methoxymeliacarpinin (meliacarpinin B) R1 =R3 =H;R2 = Tig M. azedarach 205,219,341 85,214 329 1-acetyl-3-tigloyl-11-methoxymeliacarpinin (meliacarpinin C) R1 = OAc; R2 = Tig; R3 =H M. azedarach; M. toosendan 205,219,341,346 85,214 330 1-tigloyl-3-acetyl-11-methoxymeliacarpinin (meliacarpinin D) R1 = OTig; R2 = Ac; R3 =H M. azedarach; M. toosendan 206,342 331 3-tigloyl-11-methoxymeliacarpinin (meliacarpinin E) R1 = OH; R2 = Tig; R3 =H M. azedarach
Figure 12. Structures of azadirachtinin/meliacarpinin-class limonoids 316 331. the progenitor was proposed.276 The structures of dukunolides C-8/14 in 1966596 and then was revised to be angustinolide, in A C(614 616) including their absolute configurations were which the double bond was assigned as C-8/9,597,598 to better fit established by X-ray analysis and chemical correlation.577 The its origin, but finally the original structure based on the spectro- biosynthesis of 614 was recognized by considering the inter- scopic and chemical properties was preferred.599,600 Subse- mediary mexicanolide or its analogs.578 Neotecleanins 621 625, quently, the 13C NMR signals of fissinolide were reassigned in the first natural occurrence of limonoids with a five-membered- 1998,601 and the structures of the “grandifoliolin” isolated in ring A-seco structure, might serve as intermediates in the path- 1967602 and the “3β-acetoxymexicanolide” obtained in 1999 way to the formation of tecleanin and related compounds.579 were shown to be 648.603 Gan et al. mistakenly cited khayasin 2.3.2. 2,30-linkage Group. 2.3.2.1. Mexicanolide-Class. (652)as3β-isobutyryloxymexicanolide.591 In terms of biosyn- Mexicanolide (626), first isolated as the main constituent of thetic pathway, xyloccensin N (669) was a possible intermediate Carapa procera,167 was proved to be the “substance B” from on the route to xyloccensin M (771), and they were once isolated Cedrela odorata by analysis of its spectral data.459,585 Its structure, from the same plant simultaneously as a pair of isomers of including the absolute configuration, was assigned on the basis of mexicanolides.604,605 The structure of swietenine (677) was its NMR spectral data,586 chemical reaction,587 and CD data,588 elucidated on the basis of chemical606,607 and spectroscopic and was confirmed by its crystallographic analysis.589 The struc- evidence,608,609 and confirmed by X-ray analysis of the p-iodo- ture of 632 was assigned as 6-deoxyswietenolide early in 1968,533 benzoate of detigloylswietenine610,611 and swietenine itself.612 but Sondengam et al. named it as proceranolide when they The structure of the 3β-hydroxymexicanolide (Δ8,30 instead of isolated it in 1980.590 As for 20R- and 20S-methylbutanoylprocer- Δ8,14) reported by Govindachari et al. in 1997468 was in fact anolide (633 and 634), the considerable steric interaction identical with 6-deoxydestigloylsweietenine (684), which was between the 2-methylbutanoyl group and the limonoid core reported in 1967.464 2-Hydroxy-6-deoxyswietenine (690) was made one stable conformation dominant in solution. Further- obtained early in 1988,613 and was mistakenly reported as methyl more, a general rule for the determination of the absolute 3β-tigloyloxy-2-hydroxy-1-oxo-meliac-8(30)-enate ten years configurations of 2R- and 2S-methylbutanoyl at C-3 of a limo- later.614 The structure of febrigugin (694), first obtained from noid in a mixture was proposed based on the 1H NMR con- Soymida febrifuga615 and identical with 6-deoxyswietenine from formational analysis.591 The structure of swietenolide (638) was Swietenia mahagoni,616 was incorrectly assigned,290 and its spec- elucidated on the basis of evidence from chemical properties592 594 troscopic data were revised.617 The absolute configurations of and spectroscopic data.594 The crystal structure analysis of 694 and cipadesin (703) were determined by spectroscopic and diacetylswietenolide (647) was provided by Goh et al.595 One X-ray methods.618 The mixture of methyl 2-hydroxy-3β-iso- of the double bond of fissinolide (648) was first assigned as butyroxymeliac-8(30)-enate (699) and its 3β-tiglate derivative,
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Table 11. Structures and Sources of Salannin-Class Limonoids 332 352
no. compounds substitution groups and others sources
102,104,106,107,295,316,317,357 358 332 salannin R1 = Tig; R2 = OAc; R3 =CH3 Azadirachta indica; Melia dubia; M. azedarach;142,176,219,342,359 361 M. volkensii;362 M. toosendan84,239,363 342,361,364 103,104,245,316,317 333 3-deacetylsalannin R1 = Tig; R2 = OH; R3 =CH3 M. azedarach; Azadirachta indica 365 334 1-detigloyl-1-isobutylsalannin R1 = iBu; R2 = OAc; R3 =CH3 Melia volkensii 0 0 365 335 2 ,3 -dihydrosalannin R1 = dihydrotigloyl; R2 = OAc; R3 =CH3 M. volkensii 245,366 336 salannol R1 = iVal; R2 = OH; R3 =CH3 Azadirachta indica 366,367 337 salannol acetate R1 = iVal; R2 = OAc; R3 =CH3 A. indica 0 0 368 338 2 ,3 -dehydrosalannol R1 = Sen; R2 = OH; R3 =CH3 A. indica 369 339 3-deoxymethylnimbidate R1 =R2 =H;R3 =CH3 A. excelsa 370 340 ohchinin R1 = Cin; R2 = OH; R3 =CH3 Melia azedarach 364 246 341 ohchinin acetate (ohchinin-3-acetate) R1 = Cin; R2 = OAc; R3 =CH3 M. azedarach; M. volkensii 249,250 342 nimbidic acid R1 =R3 =H;R2 =OH Azadirachta indica 343 ohchinal R = Bz Melia azedarach364 344 1-O-tigloyl-1-O-debenzoylohchinal R = Tig M. toosendan235,371 345 nimbolide R = O; Δ2,3 Azadirachta indica;102,355,372 376 A. excelsa369 346 28-deoxonimbolide R = H; Δ2,3 A. indica;373,374,377 A. excelsa;369 Owenia cepiodora378 347 2,3-dihydronimbolide R = O Azadirachta excelsa369 317,325,356 253 348 salannolide (compositolide, isosalanninolide) R1 = OTig; R2 = OAc; R3 =O;R4 =OH A. indica; Melia dubia 317,318 349 salanninolide R1 = OTig; R2 = OAc; R3 = OH; R4 =O Azadirachta indica 379 350 isoazadirolide R1 = OSen; R2 =R3 = OH; R4 =O A. indica Δ1,2 380 351 margosinolide R1 =H;R2 =R3=O;R4 = OH; A. indica Δ1,2 380 352 isomargosinolide R1 =H;R2 =R4 =O;R3 = OH; A. indica
Figure 13. Structures of salannin-class limonoids 332 352. which showed a mass peak at 556 with a less intense companion xyloccensin K (788) was elucidated by X-ray crystallography, its at 568, was very difficult to separate.619 The Δ8,9 double bond NMR data corroborated and later clarified its structure as in angustidienolide597 was revised to be Δ8,30 on the basis of featuring a tetrahydrofuran subunit with oxygen bridging from chemical and spectroscopic evidence,162,600 and then 2α-hydro- C-3 to C-8.113,627,628 Unfortunately, the structure of 793 was first xyangustidienolide was correspondingly shown as 722. Unfortu- named as humilinolide A in 1993629 and was mistakenly docu- nately, methyl 3β-acetoxy-6-hydroxy-1-oxomeliac-14-enoate mented as methyl 3β-isobutyryloxy-2,6-dihydroxy-8α,30α-epoxy- (743) reported in 1998601 was wrongly cited as 3β-acetoxy-3- 1-oxo-meliacate by Kojima et al. in 1998,614 however, methyl deoxo-6R-hydroxycarapin by Tchimene et al. in 2005.552 The 3β-tigloyloxy-2-hydroxy-8α,30α-epoxy-1-oxo-meliacate (797) structures of utilins B (749) and C (755) from the barks of reported by him in 1998614 was renamed as 2-hydroxyswiete- Entandrophragma utile, were assigned on the basis of extensive mahonolide in 2004 by another research group.630 In addition, NMR experiments and then confirmed by single crystal the same incidents occurred to 805,whichwasfirstnamedas X-ray measurements.620,621 The discovery of khayalenoids 8,30-epoxy swietenine acetate in 198355 and subsequently A-D (751-754) provided examples of limonoids containing the reported mistakenly as swietemahonin F in 1990 by Kadota 8-oxa-tricyclo[4.3.2.02,7]undecane motif.622,623 The mixture hav- et al.56 It was noteworthy to point out that two compounds, ing xyloccensins X (758) and Y (759) with interchangeable 815617 and 1051,631 were isolated in 2005 by two research substitutions of isobutyl and isopropyl group between the C-3 groups independently, and they were both named as cipadesin and C-30 positions was unequivocally assigned through the A though different skeletons were ascribed to them. Granax- HMBC spectrum.624 The spectroscopic properties of xyloccen- ylocarpin B and xylocarpin H, both of which were iso- sin F (768) assigned by Connolly et al.625 were revised on the lated from Xylocarpus granatum by two research groups in 2007, basis of extensive NMR analysis.626 Although the structure of had the same structure as 822.632,633 Xylocarponoid A (825),
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Table 12. Structures and Sources of Nimbolinin-Class Limonoids 353 390
no. compounds substitution groups and others sources α α α α 381 353 1 -tigloyloxy-3 -acetoxyl-7 -hydroxyl-12 - R1 = Tig; R2 =H;R3 = OCH2CH3 Melia toosedan ethoxyl nimbolinin α α α α 381 354 1 -benzoyloxy-3 -acetoxyl-7 -hydroxyl-12 - R1 = Bz; R2 =H;R3 = OCH2CH3 M. toosedan ethoxyl nimbolinin 85,212 355 nimbolinin A R1 = Ac; R2 = Bz; R3 =OH M. toosendan 382 85,247 356 1-deacetylnimbolinin A R1 =H;R2 = Bz; R3 =OH M. azedarach; M. toosendan 0 186 357 12-ethoxynimbolinin A R1 =2-methylacryl; R2 =H;R3 = OCH2CH3 M. toosendan 212,247 342,360,361,382 358 nimbolinin B R1 = Ac; R2 = Tig; R3 =OH M. toosendan; M. azedarach; Turraea robusta87 85,247 359 1-deacetylnimbolinin B R1 =H;R2 = Tig; R3 =OH Melia toosendan 186 143 360 12-O-methylnimbolinin B R1 =H;R2 = Tig; R3 = OCH3 M. toosendan; Turraea holstii 186 361 12-ethoxynimbolinin B R1 = Cin; R2 =H;R3 = OCH2CH3 Melia toosendan 371 362 12-O-ethyl-1-deacetylnimbolinin B R1 =H;R2 = Tig; R3 = OCH2CH3 M. toosendan 212 363 nimbolinin C R1 = Cin; R2 =H;R3 = OCH3 M. toosendan 212 364 nimbolinin D R1 =H;R2 = Bz; R3 = OCH3 M. toosendan 383 365 nimbolicin R1 = methylacryl; R2 = Cin; R3 =OH Azadirachta indica 240,383 240 384 366 nimbolin B R1 = Ac; R2 =Cin; R3 =OH A. indica; Melia azedarach; M. volkensii 385 367 nimbilin R1 = Ang; R2 = Cin; R3 =OH Azadirachta indica 386 368 heudebolin R1 =R2 = Ac; R3 =OH Trichilia heudelotii 362 369 volkensin R1 = Tig; R2 =H;R3 =OH Melia volensii 211 370 12-O-methylvolkensin R1 = Tig; R2 =H;R3 = OCH3 M. toosendan 382,387 389 371 ohchinolide A R1 = Ac; R2 = Bz; R3 =O M. azedarach 387 372 1-O-deacetylohchinolide A R1 =H;R2 = Bz; R3 =O M. azedarach 387 373 1-O-deacetyl-1-O-tigloylohchinolide A R1 = Tig; R2 = Bz; R3 =O M. azedarach 382,387,389 85 374 ohchinolide B R1 = Ac; R2 = Tig; R3 =O M. azedarach; M. toosendan; Azadirachta indica102 387 375 1-O-deacetylohchinolide B R1 =H;R2 = Tig; R3 =O Melia azedarach 387 376 1-O-deacetyl-1-O-tigloylohchinolide B R1 =R2 = Tig; R3 =O M. azedarach 387 377 1-O-deacetyl-1-O-benzoylohchinolide B R1 = Bz; R2 = Tig; R3 =O M. azedarach 390 378 chisonimbolinin A R1 =R2 = Ac; R3 = OCH3 Chisocheton paniculatus 390 379 chisonimbolinin B R1 =H;R2 = Ac; R3 = OCH3 C. paniculatus 390 380 chisonimbolinin C R1 =H;R2 = Tig; R3 = OCH3 C. paniculatus 390 381 chisonimbolinin D R1 =H;R2 = Ac; R3 =OH C. paniculatus 390 382 chisonimbolinin E R1 =H;R2 = Ac; R3 = OCH2CH3 C. paniculatus 390 383 chisonimbolinin F R1 =R3 =H;R2 =Ac C. paniculatus 390 384 chisonimbolinin G R1 =R2 = Ac; R3 =H C. paniculatus 385 12-ethoxynimbolinin C Melia toosendan186 386 ohchinolide C R = iBu M. toosendan84,85 387 azecin 2 R = H M. azedarach173 388 12-ethoxynimbolinin D M. toosendan186 389 melianolide M. azedarach361 390 17-epi-12-dehydroxyheudebolin Turreanthus africanus391
637 containing a C28 limonoid skeleton, may originate from xylo- 832 and xylogranatin D (833) were postulated in 2006, and granatin C (823) by an aldol condensation followed by intra- 833, the sole limonoid with a C-9/30 linkage, was apparently molecular hemiacetal formation.634 In addition, its ring cleavage considered to be an artifact.638 Unfortunately, the trivial names “ ” isomer (xylocarponoid B) was formed gradually in CDCl3 during xylogranatin A D were also proposed for the compounds 737 the NMR experiments and finally reached equilibrium at an A: B and 762 764 isolated in 2006.639 Xylogranatins I-Q (834-842) ratio of 4:1.634 Compound 829, possessing a highly oxidized all contained a central furan core, and they were derivated from heptacyclic A,B,D-seco limonoid with an 8α,30α-epoxy ring and the key biosynthetic intermediates xylogranatins C and R (823 1,29-oxygen bridge, was patented as xylolactone635 and then was and 843).638 The possible biosynthetic pathway of grandifotane named xyloccensin L636 in Tetrahedron Letters in 2004 by A(845) was postulated, in which an intermediate was formed Wu et al. The structure of xylogranatin A (832), featuring a from a mexicanolide-type limonoid by an enzymatic Baeyer 1,9-oxygen bridge, was confimed by X-ray diffraction analysis.637 Villiger oxidation. Then, the intermediate might undergo serials The hypothetical biosynthetic route and chemical correlations of of reactions to keep the required stereochemistry for 845.640
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Figure 14. Structures of nimbolinin-class limonoids 353 390.
Table 13. Structures and Sources of Nimbin-Class Limonoids 391 404
no. compounds substitution groups and others sources
59,70,81,102 106,115,136,317,325,357,405 407 391 nimbin R1 = COOCH3;R2 =Ac Azadirachta indica 70,81,102 104,106,317,325,407,408 392 6-deacetylnimbin R1 = COOCH3;R2 =H A. indica 367 393 nimbanal R1 = CHO; R2 =Ac A. indica 377 394 6-deacetylnimbanal R1 = CHO; R2 =H A. indica 377 395 nimbinol R1 =CH2OH; R2 =Ac A. indica 342,360,370,387 396 ohchinolal (salannal) R1 = Tig; R2 =H Melia azedarach 387 397 1-O-detigloyl-1-O-benzoylohchinolal R1 = Bz; R2 =H M. azedarach 387 398 1-O-detigloyl-1-O-cinnamoylohchinolal R1 = Cin; R2 =H M. azedarach 84,85 399 3-O-acetylohchinolal R1 = Tig; R2 =Ac M. toosendan 408 400 desacetylnimbinolide R1 =H;R2 =O;R3 =OH Azadirachta indica 409 401 isonimbinolide R1 = Ac; R2 = OH; R3 =O A. indica 408 402 desacetylisonimbinolide R1 =H;R2 = OH; R3 =O A. indica 403 4-epi-nimbin A. indica410 404 7α-hydroxy-15β-hydroxy-7,15-deoxo nimbin A. indica411
Figure 15. Structures of nimbin-class limonoids 391 404.
2.3.2.2. Phragmalin-Class. 2.3.2.2.1. Phragmalin-ortho Es- decane, and most of them also bore an ortho ester group. Up to ters. Phragmalin-class limonoids possessed characteristic rings of now, four subtypes of phragmalin orthoesters have been reported, A and B tricyclo[3.3.12,10.11,4]decane or tricyclo[4.2.110,30.11,4]- which were classified into 1,8,9- ( -910), 8,9,11- (911 916),
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Table 14. Structures and Sources of Nimbolidin-class 405 415
no. compounds substitution groups and others sources
382 405 nimbolidin A R1 =R3 = Ac; R2 =Bz Melia azedarach 226 406 15-O-deacetyl-15-O-methylnimbolidin A R1 = Ac; R2 = Bz; R3 =CH3 M. azedarach 342,361,382 209,363 407 nimbolidin B R1 =R3 = Ac; R2 = Tig M. azedarach; M. toosendan 226 408 15-O-deacetylnimbolidin B R1 = Ac; R2 = Tig; R3 =H M. azedarach 226 409 15-O-deacetyl-15-O-methylnimbolidin B R1 = Ac; R2 = Tig; R3 =CH3 M. azedarach 85,363 410 nimbolidin C R1 =R3= Ac; R2 = iBu M. toosendan 85,363 411 nimbolidin D R1 =R2= Tig; R3 =Ac M. toosendan 85,363 412 nimbolidin E R1 = Tig; R2 = iBu; R3 =Ac M. toosendan 84,85 413 nimbolidin F R1 = Piv; R2 = Tig; R3 =Ac M. toosendan 414 walsogyne A Walsura chrysogyne412 415 7α-acetyl-15β-methoxy-29- methylene-7,15-deoxonimbolide Azadirachta indica411
Figure 16. Structures of nimbolidin-class 405 415.
8,9,14- (917 930), and 8,9,30-phragmalin orthoesters (931 962) of utilin (920), possessing the 1,29-cycloswietenan skeleton, was according to the position of the ortho-acetate group. The struc- confirmed by X-ray analysis, and its absolute configuration was ture of phragmalin (846) was proposed on the basis of chemical established by chemical methods.698 The structure of xyloccensin and spectroscopic evidence689 and then determined by means of O(948), the first example of an 8,9,30-phragmalin orthoester an X-ray study of its iodoacetate.690 The distribution of phrag- limonoid, was confirmed by X-ray crystallographic analysis, and a malins and mexicanolides in the stem barks, fruits, and seeds of biosynthetic pathway to it from mexicanolide was proposed.699 the Chinese mangrove plant Xylocarpus granatum was discussed, The structures of some xyloccensins from Xylocarpus granatum and the conclusion was reached that the high concentration of were not in accord with the nomenclatures used by different phragmalin orthoesters in the stem barks of Xylocarpus plants research groups, which led to great confusion. On one hand, the might serve as an important chemical defense aginst invasion by structures of xyloccensins Q (950), R (951), and V (955) pests or microorganisms.633 A biosynthetic route to 846 which obtained by Wu et al.639,659,700 were identical to xyloccensins could explain why 1,29-cycloswietenan derivatives were hydro- R, Q, and T reported by Cui et al.,701 respectively. On the other xylated at C-8 and C-9 was presented.683 The structure of 850 hand, both 954659,700 and 987701 were named xyloccensin U. was assigned as xyloccensin E early in 1976,625 and was obtained 2.3.2.2.2. Polyoxyphragmalins. Unfortunately, in 2010, two and then reported as phragmalin 2,3,30-triacetate in 1992.162 The separate groups selected the trivial names moluccensins H Jto substance ‘bussein’ obtained from Entandrophraga bussei,424,530 was apply to six compounds (963 968) with the same skeleton but showntobeamixtureofbusseinsA(865)andB(866), whose different substitutions, which caused each trivial name to corre- structures were first assigned on the basis of spectroscopic spond to two different structures (Figure 27 and Table 25). In properties and chemical reactions691 and then were subse- fact, the structures of xylocarpins A (981) and D (984) obtained quently modified.692,693 The 1H NMR-based conformational from Xylocarpus granatum and elucidated in 2007,633 were the analysis on the epimeric compounds swietenitins A and B (897 same as granaxylocarpins E and D, respectively, obtained from and 898) provided a general approach to determining the absolute the same species in the same year.632 The structure of xyloccensin configuration of the 2,3-epoxy-2-methylbutyryloxy unit borne at U, isolated from X. granatum,701 was revised to be 987 by analysis C-3 by a large group of the phragmalin-orthoester limnoids.456 The of its HMBC data and analogous comparison.632,633 From a structure of pseudrelone B (903)fromPseudocedrela kotschyii694 biosynthetic perspective, atomasins such as atomasins A and B was revised to have C-11/19 instead of C-11/18 ether bridge based (974 and 975) from Entandrophragma candollei719 and 8,9- on the X-ray analysis of its triacetate.695 It was suggested on the dihydroxy phragmalins, such as tabulalides A and B (995 basis of a plausible proposed biosynthetic origin that chukvelutilides and 996) from Chukrasia tabularis,706 were the precursor of A-F (904 909), which have a C-16/30 lactone ring, also have a the phragmalin orthoesters. The extensive spectroscopic analyses three- or four-carbon enolized acyl substituent at C-15.696 Chuk- including MS, NMR, and single crystal X-ray diffraction experi- tabrin B (910) had a polycyclic skeleton containing a 4,5,6,7- ments suggested that methyl lα-acetoxy-6,8α,14β,30β-tetrahy- tetrahydrobenzofuran formed via a cyclization reaction between droxy-3-oxo-[3.3.110,2.11,4]-tricyclomeliac-7-oate (992)720 and C-15 and C-21, a δ-lactone furnished between C-16 and C-30, methyl lα,6,8α,14β,30β-pentahydroxy-3-oxo-[3.3.110,2.11,4]-tri- and a biosynthetically extended C2 unit at C-15.697 The structure cyclomeliac-7-oate (991)721 were, in fact, khayanolide E (1007)
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Table 15. Structures and Sources of Ring D-seco Limonoids 416 457
no. compounds substitution groups and others sources
423 424,425 416 gedunin R1 =R3 =H;R2 = OAc Entandrophragma angolense; E. delevoyi; Xylocarpus granatum;49,424,426,427 X. obovatus;428 Azadirachta indica;57 59,70,80 82,103,104,107,115,240,429 Trichilia trifolia;182 Cabralea eichleriana;430 Melia azedarach;240,251 Cedrela fissilis;113,132 C. odorata;98,431,432 C. sinensis;433 Guarea grandiflora;434,435 Khaya grandifoliola;436 Chisocheton paniculatus;117 Carapa guianensis113,437 α α 137 417 6 -hydroxygedunin R1 = -OH; R2 = OAc; R3 =H C. guianensis α α 113,137,437,438 fi 113 418 6 -acetoxygedunin R1 = -OAc; R2 = OAc; R3 =H C. guianensis; Cedrela ssilis; Chisocheton paniculatus;94,117 Swietenia mahagoni;112 Guarea grandiflora;434 Aglaia elaeagnoidea419 α β α β 439 438,440 419 6 ,11 -diacetoxygedunin R1 = -OAc; R2 = OAc; R3 = -OAc A. elaeagnoidea; Carapa guianensis; C. granatum441 β β 442 420 6 -hydroxygedunin R1 = -OH; R2 = OAc; R3 =H Azadirachta indica 57,70,103,104 fi 113 98 421 7-deacetylgedunin R1 =R3 =H;R2 =OH A. indica; Cedrela ssilis; C. odorata; C. sinensis;433 Pseudocedrela kotschyi;443,444 Trichilia trifolia;182 Swietenia aubrevilleana;445 Khaya ivorensis;446,447 K. grandifoliola;164 Cabralea eichleriana;430 Carapa guianensis;437 Xylocarpus granatum448 68,70 422 7-desacetyl-7-benzoylgedunin R1 =R3 =H;R2 =Bz Azadirachta indica 113,137,437,449,450 423 7-deacetoxy-7-oxogedunin R1 =R3 =H;R2 =O Carapa guianensis; Pseudocedrela kotschyii;443,444 Khaya senagalensis;164,451 K. ivorensis;446,447 Melia azedarach;251,452 Trichilia schomburgkii;453 Guarea grandiflora;434,435 G. guidona;454 Cabralea eichleriana;430 Xylocarpus granatum;448,455 X. moluccensis;162 Swietenia macrophylla;445,456 S. mahagoni;112,457,458 Cedrela fissilis;113,132 C. odorata98,167,459 α β β 433 424 7-deacetoxy-7 ,11 -dihydroxygedunin R1 =H;R2 = OH; R3 = -OH C. sinensis α α α 433 425 7-deacetoxy-7 ,11 -dihydroxygedunin R1 =H;R2 = OH; R3 = -OH C. sinensis α α 433 426 11 -hydroxygedunin R1 =H;R2 = OAc; R3 = -OH C. sinensis β β 433 427 11 -hydroxygedunin R1 =H;R2 = OAc; R3 = -OH C. sinensis β β 440 425 428 11 -acetoxygedunin R1 =H;R2 = OAc; R3 = -OAc Carapa guianensis; Entandrophragma delevoyi 433 429 11-oxogedunin R1 =H;R2 = OAc; R3 =O Cedrela sinensis 460 430 7α-acetoxy-14β,15β-epoxygedunan-1- R=β-D-Glc Melia azedarach ene-3-O-β-D-glucopyranoside 173 431 azecin 4 R = β-D-Ara M. azedarach 432 7-deacetoxy-7-hydroxyphotogedunin R = H Cabralea eichleriana430 433 photogedunin R = Ac Cedrela fissilis;113 C. salvadorensis;413,420 C. dugessi;413 C. odorata;461 C. ciliolata;462 Xylocarpus granatum427 446,463 163,183 434 khivorin R1 =R2 =R3 = OAc; R4 =H Khaya ivorensis; K. anthotheca; K. grandifolia;164,167 K. senegalensis;451,464 466 K. nyasica;184 Swietenia mahagoni458 458 436 435 1-deacetylkhivorin R1 = OH; R2 =R3 = OAc R4 =H S. mahagoni; Khaya grandifoliola 464 468 163,183 436 3-deacetylkhivorin R1 =R3 = OAc; R2 = OH; R4 =H K. senegalensis; K. anthotheca; K. nyasica;184 K. madagascariensis;164,469 K. ivorensis;447 Swietenia mahagoni458 458 436 437 7-deacetylkhivorin R1 =R2 = OAc; R3 = OH; R4 =H S. mahagoni; Khaya grandifoliola
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Table 15. Continued no. compounds substitution groups and others sources 447 470,471 438 1,3,7-trideacetylkhivorin R1 =R2 =R3 = OH; R4 =H K. ivorensis; K. senegalensis; Swietenia mahagoni458 465,466,468,472 439 3-deacetyl-7-oxokhivorin R1 = OAc; R2 = OH; R3 =O;R4 =H Khaya senegalensis α α 164,422,467,468,470,473 440 3 ,7 -dideacetylkhivorin R1 = OAc; R2 =R3 = OH; R4 =H K. senegalensis; K. ivorensis;447 Swietenia mahagoni458 164,167,451,464,465 441 7-deacetoxy-7-oxokhivorin R1 =R2 = OAc; R3 =O;R4 =H Khaya senegalensis β 469,474 164,184 442 11 -acetoxykhivorin R1 =R2=R3 =R4 = OAc K. madagascariensis; K. nyasica 167,475 443 dihydrogedunin R1 =R4 =H;R2 =O;R3 = OAc Guarea thompsonii α 475 444 7-oxodeacetoxydihydro- -gedunol R1 =R4 =H;R2 = OH; R3 =O G. thompsonii α 49 445 1 -hydroxy-1,2-dihydrogedunin R1 = OH; R2 =O;R3 = OAc; R4 =H Xylocarpus granatum α 98 446 1 -methoxy-1,2-dihydrogedunin R1 = OCH3;R2 =O;R3 = OAc; R4 =H Cedrela odorata 184,476,477 447 nyasin R1 =R2 =R3 = OAc; R4 =OH Khaya nyasica 448 1,2-dihydro-3β-hydroxy-7-deacetoxy- Cedrela fissilis;113 C. guianesnsis113 7-oxogedunin 449 azadirinin Azadirachta indica478 450 3,7-dideacetyl-6α-hydroxykhivorin Khaya senegalensis466 451 nimolicinol R = Ac; Δ1,2 Azadirachta indica70,115,479 452 7-deacetynimolicinol R = H; Δ1,2 A. indica115 453 1α,2α-epoxynimolicinol R = Ac; 1,2-epoxy A. indica115 454 mahmoodin A. indica81 455 piscidofuran Walsura piscidia88 456 meliacinol Azadirachta indica93 457 Melia azedarach480
Figure 17. Structures of ring D-seco limonoids 416 457. and 1-O-deacetylkhayanolide E (1008) respectively.722 Swiema- destroyed.572 The biosynthesis of trichiliton A (997), bearing hogin B (993) was an example of incorporating a rare five- a bicyclo[5.2.14,10]decane motif, involved an alternative new route membered γ lactone fused to the C-ring at C-8 and C-14 from mexicanolide to phragmalin.651 Khayalactone (998)could and in which the six-membered δ-lactone in the D-ring was arise from a 1,2,3,8-tetrahydroxylated precursor by cleavage of the
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Figure 18. Structures of prieurianin-class limonoids 458 493.
1,2-diol followed by formation of the hemiketal by addition of the were,infact,khayanolideB(1004)and1-O-acetylkhayano- 8-hydroxyl group to the newly formed 1-carbonyl group.553,680 The lide B (1005),722 respectively. absolute configuration of khayanolide A (1002)wasestab- 2.3.3. 8,11-Linkage Limonoids (Trijugin-Class). Trijugin- lished by X-ray analysis and a CD study.548,549 In biosynthetic class limonoids with contracted ring C were postulated to be terms, a pinacol pinacolone rearrangement of a 2,3,30-trihy- produced biosynthetically via a pinacol pinacolone rearrange- droxyl-1,29-cyclomeliacate precursor is possible, resulting in ment of a methyl 9, 11-dihydroxyangolensate.563,565,729 Capen- a 2-oxo-tricyclo-[4,2,110,30.11,4]-decane, and subsequently re- solactones 2 and 3 (1034 and 1022) were isolated as a mixture duction or addition of an hydroxyl group at C-14 to the ketone with their ester moieties interchanged at C-2α and C-3α.730 and O-2-methylation may then led to the limonoids 1013 and Trichilin B (1043), featuring a 9,17-oxygen bridge and a highly 1015,respectively,720 which gives a further enlargement of the rearranged ring system, along with the biosynthetically correlated biosynthetic mexicanolide pathways.721 In addition, a possible trichilin A (1036), was isolated from Trichilia connaroides.731 biosynthetic pathway leading to the formation of khayanolides Unfortunately, the two trivial names were previously assigned to frommexicanolide was proposed.549 On the basis the extensive intact limonoids 137 and 135, respectively.194,732 spectroscopic analyses including MS, NMR, and single crystal 2.3.4. 10,11-Linkage Limonoids (Cipadesin-Class). The X-ray diffraction experiments, Zhang et al. proposed that rings A and C of cipadesin-class limonoids were joined via C-10/ methyl lα,2β,3α,6,8α,14β-hexahydroxy-[4.2.110,30.11,4]-tricy- 11, and among these limonoids the structure of cipadesin C clomeliac-7-oate (1014)andmethyllα-acetoxy-2β,3α,6,8α,14β- (1044) was confirmed by X-ray crystallographic analysis.631 Two pentahydroxy-[4.2.110,30.11,4]-tricyclomeliac-7-oate (1015)721 compounds found in Cipadesa cinerascens, 103954,563 and 1045,53
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Table 16. Structures and Sources of Prieurianin-Class Limonoids 458 493
no. compounds substitution groups and others sources
168 454 458 prieurianin R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl; Trichilia prieuriana; Guarea guidona; 283 189 R3 =O;R4 = OAc; R5 =CH3 Nymania capensis; Turraea obtusifolia; Entandrophragma candolei491 484 459 rohituka 4 R1 = formacyl; R2 = iVal; R3 =O;R4 = OAc; R5 =CH3 Aphanamixis polystacha 274 460 dregeana 2 R1 =R2 = Ac; R3 =O;R4 =H;R5 =CH3 Trichilia dregeana 492 461 trichavensin R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl; T. havanensis
R3 = OAc; R4 = pivalyloxy; R5 =CH3 493 462 Tr-A R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl; T. roka
R3 = OAc; R4 = OH; R5 =CH2CH3 493 463 Tr-C R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl; T. roka
R3 = OAc; R4 = OH; R5 =CH3 454 494 464 expoxyprieurianin R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl; Guarea guidona; Entandrophragma candolei
R3 =H;R4 = OAc 483 465 dysoxylumin A R1 = formacyl; R2 = iVal(OH); R3 = OPiv; R4 = OAc Dysoxylum hainanense 483 466 dysoxylumin B R1 = formacyl; R2 = iVal(OH); R3 = iVal(OAc); R4 = OAc D. hainanense 483 266 467 dysoxylumin C R1 = formacyl; R2 = iVal(OH); R3 = OiVal(OH); R4 = OAc D. hainanense; D. lenticellatum 283 468 nymania 4 R1 =R2 = Ac; R3 =R4 =H Nymania capensis 484 469 rohituka 8 R1 = formacyl; R2 = iVal; R3 = OH; R4 = OAc; R5 = OAc Aphanamixis polystacha 495 470 mombasone R1 = formacyl; R2 = 2-oxo-3-methylpentanoyl; R3R4 =O;R5 = OAc Turraea mombasana 495 496 471 mombasol R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl; T. mombasana; Guarea guidona
R3R4 =O;R5 = OAc 279 472 amotsangin A R1 = Ac; R2 = Piv; R3R4 =O;R5 =H Amoora tsangii 279 473 amotsangin B R1 = Ac; R2 = iBu; R3R4 =O;R5 =H A. tsangii 279 474 amotsangin C R1 = Ac; R2 = 2-hydroxy-3-methylpentanoyl; R3R4 =O;R5 =H A. tsangii 279 475 amotsangin D R1 = Ac; R2 = propanoyl; R3R4 =O;R5 =H A. tsangii 279 476 amotsangin E R1 = Ac; R2 = Bz; R3R4 =O;R5 =H A. tsangii 279 477 amotsangin F R1 = formacyl; R2 = Bz; R3R4 =O;R5 =H A. tsangii 497 283 478 nymania 3 R1 =R2 = Ac; R3R4 =O;R5 =H Dysoxylum malabaricum; Nymania capensis 479 Tr-B R = 2-hydroxy-3-methylpentanoyl Trichilia roka;493 T. emetica;192 Apanamixis ploystacha485 480 rohitukin R = iVal A. ploystacha;484,487 Turraea obtusifolia498 481 20-hydroxyrohitukin R = iVal(OH) Guarea cedrata499 482 guarea B G. multiflora;500 G. thompsonii489 β 275,484,485 483 rohituka 7 R1 = 2-hydroxy-3-methylpentanoyl; R2 = -OAc Aphanamixis polystacha β 275,484 484 rohituka 9 R1 = iVal; R2 = -OAc A. polystacha α 501 485 hispidin B R1 = 2-hydroxy-3-methylpentanoyl; R2 = -OTig Trichilia hispida α 501 486 hispidin C R1 = 2-hydroxy-3-methylpentanoyl; R2 = -OAc T. hispida 487 D-4 T. prieuriana489 488 dregeanin T. dreageana;487 T. heudelottii77 489 cipadessalide Cipadessa baccifera282 490 rohituka 1 R = iVal Aphanamixis polystacha484 491 rohituka 2 R = 2-hydroxy-3-methylpentanoyl A. polystacha484 492 gaudichaudysolin A Dysoxylum gaudichaudianum502 493 D-5 Trichilia prieuriana489 had both been given the trivial name cipadesin E. Fang et al. 2.3.5. Other Linkages Group. The structure of walsuronoid postulated that cipadonoids C G(1046 1050) might be A(1054), featuring a 3,4-peroxide bridge A-seco skeleton and a biosynthetically derived from the methyl angolensate-class limo- C-3/19 linkage bridge, was confirmed by single-crystal X-ray noid via a pinacol rearrangement, which was confirmed by a diffraction.739 The hypothetical biosynthesis route from 11β- computational study at the DFT level with a B3LYP/6-31G basis hydroxycedrelone (82) to walsuronoids B (1058) and C (1059), set as well as by chemical transformation. In addition, the which have the 18 (13f14) abeo limonoid skeletons, and the presence of a Δ8,30 double bond in the methyl angolensate chemical correlations between them were proposed.739 The precursor led to trijugin-class limonoids while its absence led to structure of delevoyin C (1060), possessing a cyclobutanyl ring cipadesin-class limonoid.544 incorporating C-19 and a cycloheptanyl ring C including C-30,
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Table 17. Other Structures and Sources of Rings A,B-seco Limonoids 494 524
no. compounds substitution groups and others sources
494 toonaciliatin E R = OAc Toona ciliata290 495 toonaciliatin H R = H T. ciliata290 496 toonaciliatin I T. ciliata290 497 surenolactone T. sureni505 506 498 munronin A R1 =O;R2 =OH Munronia henryi 506 499 munronin B R1 = OH; R2 =O M. henryi 506 500 munronin C R1 =O;R2 =H M. henryi 501 dysoxylumolide B R = 2-hydroxy-3-methylpentanoyl Dysoxylum hainanense507 502 dysoxylumic acid D R = 2-hydroxy-3-methylpentanoyl D. hainanense507 503 dysoxylumic acid A D. hainanense507 504 dysoxylumic acid B D. hainanense507 505 rohituka 6 Aphanamixis polystacha484 506 dysoxylumic acid C Dysoxylum hainanense507 192 484,485 507 rohituka 3 R1 = 2-hydroxy-3-methylpentanoyl; R2 = OH; R3 =O;R4 =H Trichilia emetica; Aphanamixis polystacha 484,485 508 rohituka 5 R1 = 2-hydroxy-3-methylpentanoyl; R2 = OH; R3 =OAc; R4 =H A. polystacha 275 509 rohituka 13 R1 = iVal; R2 = OH; R3 =OAc; R4 =H A. polystacha 275,485 510 rohituka 14 R1 = iVal; R2 = OH; R3 =O; R4 =H A. polystacha 489 511 R1 = formacyl; R2R3 =O;R4 =H Trichilia prieuriana 507 512 dysoxylumolide A R1 = iVal(OH); R2R3 =O;R4 = OiVal(OH) Dysoxylum hainanense 513 toonaciliatin D Toona ciliata290 274 485,508 514 dregeana 1 R1 = formacyl; R2 = 2-hydroxy-3-methylpentanoyl Trichilia dregeana; Aphanamixis polystachya 275 515 rohituka 12 R1 =H;R2 = iVal A. polystacha 485,508 516 rohituka 15 R1 =H;R2 = 2-hydroxy-3-methylpentanoyl A. polystacha 275,503 517 polystachin R1 = formacyl; R2 = iVal A. polystacha 504 518 rubrin A R1 = OH; R2 = OPiv Trichilia rubra 504 519 rubrin B R1 = OH; R2 = OiBu T. rubra 501 504 520 hispidin A (rubrin C) R1 = OH; R2 = OTig T. hispida; T. rubra 504 521 rubrin D R1 = OH; R2 = propanoylate T. rubra 504 192 509 522 rubrin E (nymania 1) R1 = OH; R2 =O T. rubra; T. emetica; T. obtusifolia 504 523 rubrin F R1 =O;R2 = OAc T. rubra 504 524 rubrin G R1 = OH; R2 = OAc T. rubra was suggested by the LSD (Logic for Structure Determination) postulated.750 The structure of chuktabrin A (1097), featuring program.425 The absolute configurations of cipadonoid A (1061), motifs of a 1,3-dioxolan-2-one and a 3,4-dihydro-2H-pyran which featured a tetrahydropyranyl ring B and characterized by a formed via an ether bond between C-30 and C-1 in the bio- C-30 exomethylene group inserted between C-8 and C-10,740 was synthetically extended C3 unit at C-15, was confirmed by X-ray revisedtobe1S,3R,5S,8S,10R,13S,14R,17R.741 diffraction.697 The co-occurrence of limonoids and norlimonoids in Toona ciliata together with the possible mechanisms of 2.4. Limonoids Derivatives conversion suggested a biosynthetic map that encompassed the 2.4.1. Pentanortriterpenoids, Hexanortriterpenoids, pathways for all limonoids started from the common precursor Heptanortriterpenoids, Octanortriterpenoids, and En- 14,15-deoxyhavanensin.290 neanortriterpenoids Derivatives. A possible degradation In biosynthetic terms, carapolide A (1115) could be derived pathway for 2-oxo-deacetyl salannin (1063), the sole C-2 from a spiro-precursor through pathway involving a retro-prins degraded limonoid, was not proposed or hypothesized.411 Aza- reaction, cleavage and protonation.581 A limonoid belonging to dirachtin L, obtained by Kanokmedhakul et al. in 2005,324 was in the 1,8,9-orthoesters phragmalin-class might biosynthetically fact reported as marrangin (1067) early in 1993.746 The structure undergo insertion of an isobutyryl group from C-30 to C-15 of 1068 was assigned as 11α-hydroxy-12-norazadirachtin747 in through a Claisen reaction, cleavage of the C-16/17 δ-lactone, 1994, but Ramji et al. isolated and mistook it as 11-epiazadir- and then decarboxylation and de-ortho-acetation to form another achtin H748 in 1996, and Kanokmedhakul et al. isolated and intermediate, which, after a series of ketal formations and named it as 11α-azadirachtin H in 2005.324 11-epiazadirachtin I esterifications, gives chukvelutins A C(1086 1088).751 Simi- (1070) was characterized by both NMR and X-ray crystal- larly, chuktabularins E T(1090 1095, 1075, 1079 1085, lography techniques.749 Chuktabularins A D(1074, 1096, 1076, 1077) possessed a biosynthetically extended propionyl 1078, and 1089) are four 16-norphragmalin-class limonoids with or acetyl group at C-15 and a characteristic ketal moiety bet- a biosynthetically extended C2 or C3 unit at C-15 forming a ween the limonoid skeleton and the acyl substituent at unique 2,7-dioxabicycl[2.2.1]heptane moiety. Moreover, a plau- C-15.752 Ceramicine A (1118) could be transformed from limo- sible biosynthetic origin of chuktabularins A D was also noids skeleton via oxidation at C-28 and C-29 followed
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Figure 19. Other structures of rings A,B-seco limonoids 494 524. by decarboxylation.412 Two degraded limonoids, assigned as 7α- lation while the γ-lactone would be formed by esterification acetoxy-4,4,8-trimethyl-5α-(13αMe)-17-oxa-androsta-1,14- between C-7 and C-10.726 dien-3,16-dione (1130) and 7α-acetoxy-4,4,8-trimethyl-5α-17- oxa-androsta-1,14-dien-3,16-dione (1131) in 1992,753 were iso- lated and reported as 13α-nimolactone and 13β-nimolactone in 3. CHEMOTAXONOMIC SIGNIFICANCE OF MELIACEOUS 1994,107 respectively. LIMONOIDS 2.4.2. Simple Degraded Derivatives. Trichiconnarins A As one of many types of natural products in plants, the and B (1139 and 1140) are degraded limonoids with a con- limonoids were significant chemotaxonomic markers of Melia- tracted five-membered ring-C. Of these, 1139 is likely to be the ceae, Rutaceae, and Simarubaceae. A wonderful review presented degradation products of trijugin C (1111)bycleavageoftheC-2 in 1983 treated the chemotaxonomic significance of limonoids in and C-8 bonds, and 1140 is then derived from reaction of 1139 with Meliaeae and discussed the biosynthesis, distribution, and sys- acetone through an aldol reaction followed by dehydration.573 X-ray tematic significance of limonoids in the Meliaceae, Cneoraceae, analysis of 9β-bromofraxinellone has defined the absolute stereo- and allied taxa.15 Up until the present, the chemotaxonomy chemistry of fraxinellone (1142).763 significances of limonoids for Meliaceae focused mainly on the 2.4.3. N-Containing Derivatives. Microbes, such as endo- subfamily Swietenioideae and Melioideae. phytic fungi, may contribute to the biosynthesis of turrapubesin Different research groups have proposed the chemotaxonomic B(1153), which contains a maleimide ring.287 Wu et al. pro- significance of genera Khaya, Soymida, Neobeguea, Swietenia, posed a new biosynthetic pathway with xylogranatin R (843)asa Toona, and Cedrela of subfamily Swietenioideae. The western key intermediate to reach the limonoids xylogranatins F H and eastern forms of Khaya anthotheca were different chemically (1156 1158), which bear a novel skeleton with a pyridine in that the western variety gave no ring D-expanded meliacins, in ring.638 Cui et al. suggested that granatoine (1159) could be contrast to the other species.164 The timber of Soymida febrifuga biosynthetically derived from the precursor 9,10-seco-mexicano- contained no detectable level of limonoids and the bark con- lide xylogranatin C (823) via a pathway in which the pyridine tained ∼0.1% methyl angolensate (568). These results showed ring would be formed through ring condensation and dehydroxy- that Soymida was closely related to the African genus Khaya.767
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Table 18. Structures and Sources of Rings A,D-seco Limonoids 525 555 no. compounds substitution groups and others sources
515 182 525 obacunol R1 =R2 =R3 =R4 =H Lovoa trichiliodes; Trichilia trifolia α α 516 517 526 6 -acetoxyobacunol acetate R1 = -OAc; R2 = Ac; R3 =R4 =H Dysoxylum spectabile; D. richii; D. muelleri;518 Cedrela sinensis519 β β 510 527 11 -acetoxyobacunyl acetate R1 =R4 =H;R2 = Ac; R3 = -OAc C. odorata β β 510 528 11 -acetoxyobacunol R1 =R2 =R4 =H;R3 = -OAc C. odorata β β 182 529 6 -acetoxyobacunol R1 = -OAc; R2 =R3 =R4 =H Trichilia trifolia 517 530 dysoxylone R1 =O;R2 = iVal(OH); R3 =R4 =H Dysoxylum richii β α β 511 531 11 -hydroxy-7 -obacunyl acetate R1 =R4 =H;R2 = Ac; R3 = -OH Cedrela sinensis α 511 532 11-oxo-7 -obacunol R1 =R2 =R4 =H;R3 =O C. sinensis α 511 533 11-oxo-7 -obacunyl acetate R1 =R4 =H;R2 = Ac; R3 =O C. sinensis α 519 534 7 -obacunyl acetate R1 =R3 =R4 =H;R2 =Ac C. sinensis α β 145 535 perforin A R1 =R3 = -OAc; R2 = Ac; R4 = -OAc Toona ciliata 536 11β-acetoxyobacunone Trichilia elegans165 520 537 kihadanin A R1 =R3 =O;R2 =OH T. elegans ssp. elegans α α 512 538 7-deoxo-7 -hydroxykihadanin A R1 = -OH; R2 = OH; R3 =O T. elegans ssp. elegans α α 512,520 539 7-deoxo-7 -acetoxykihadanin A R1 = -OAc; R2 = OH; R3 =O T. elegans ssp. elegans β β 512 540 7-deoxo-7 -hydroxykihadanin A R1 = -OH; R2 = OH; R3 =O T. elegans ssp. elegans β β 512 541 7-deoxo-7 -acetoxykihadanin A R1 = -OAc; R2 = OH; R3 =O T. elegans ssp. elegans 520 542 kihadanin B R1 =R2 =O;R3 =OH T. elegans ssp. elegans α α 520 543 7-deoxo-7 -acetoxykihadanin B R1 = -OAc; R2 =O;R3 =OH T. elegans ssp. elegans β β 512 544 7-deoxo-7 -hydroxykihadanin B R1 = -OH; R2 =O;R3 =OH T. elegans ssp. elegans β β 512 545 7-deoxo-7 -acetoxykihadanin B R1 = -OAc; R2 =O;R3 =OH T. elegans ssp. elegans 546 7α-acetoxydihydronomilin R = H Xylocarpus granatum;513,514 Cedrela sinensis;519 C. odorata510 547 11β-hydroxyceorin G R = OH C. sinensis511 548 11-oxocneorin G R = O C. sinensis511 549 7α,11β-diacetoxydihydronomilin R = OAc C. mexicana;521 C. odorata510 550 cedrellin C. sinensis519 551 11β,19-diacetoxy-1-deacetyl-1-epidihydronomilin C. odorata510 552 dysoxylin R = H Dysoxylum richii517,522 553 tigloyldysoxylin R = Tig D. richii517 554 dysoxylumolide C D. hainanense507 555 odoralide Cedrela odorata510
Zhang et al. concluded that the configuration at C-6 of mex- precursors of the mexicanolide-class limonoids which were common icanolides, phragmalins, and khayanolides from Khaya senega- in Cedrela, suggesting a direct derivation of Cedrela from Toona-like lensis had a 6S configuration while those from Swietenia species ancestors.140 YetLiaoetal.supportedToona as a separate subfamily had a 6R configuration, and then pointed out this difference because of the biosynthetic relationship between the limonoids from implies a significant chemotaxonomy difference between the Toona ciliata and the occurrence of mexicanolide-class limonoids in African mahogany genus Khaya and the genuine mahogany this speices.290 genus Swietenia.722 Six phragmalin-class limonoids from Swiete- The chemotaxonomic significance of limonoids for genera nia macrophylla showed significant chemotaxonomic evidence in Ekebergia, Nymania, Trichilia, Turraea, Astrotrichilia, Dysoxylum, favor of linking this speices with S. mahagoni.716 Furthermore, Malleastrum, and Cipadessa ascribed to subfamily Melioideae Wu et al. described the distribution of kinds of phragmalin were also investigated extensively. The limonoids of Ekebergia orthoesters in Xylocarpeae and Swietenieae and pointed out that were not far removed from the general pattern found in the two tribes were closely related subfamilies in Meliaceae.659 The Trichileae, in which highly oxidized ring B fissioned limonoids chemotaxonomic significances of limonoids in Toona and Cedrela appeared to be the most common terpenoid constituents.567 were hot topics for years. Agostinho et al. objected to the affiliation Since trijugin-class limonoids were obtained both from Heynea of Toona to Swietenioideae by the occurrence of the meliacin trijuga and Ekebergia terophylla, the possible relationship between butenolides in both Toona and Trichilia.154 In addition, Neto and Ekebergia and Heynea was proposed.565 Because of the structural da Silva et al. pointed out that Toona differed notably from other relation between astrotrichilin (566) and ekebergin (588), genera of Swietenioideae by the absence of the mexicanolide- Mulholland et al. proposed a relationship between Astrotrichilia class limonoids and the presence of limonoids rather typical of and Ekebergia,543 which disagreed with Pennington’s view- Melioideae, and thus showed a less pronounced relationship to point.769 Chemically, Ekebergia itself was rather distinct and the Swietenioideae.161,768 Neto et al. pointed out that the ring not closely related to Trichilia so that it seemed possible that B-seco limonoids of Toona couldbeconsideredthebiosynthetic both Quivisianthe and Ekebergia occupy positions on the fringes
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Figure 20. Structures of rings A,D-seco limonoids 525 555. of the main groups of the Meliaceae, perhaps without especially precursor of a B-seco-limonoid, supported the proposition that close relation to any other genera.613 The limonoids from it would be preferred to include the genus Dysoxylum in the Nymania were typical of those from species of the genera Guarea, subfamily Melioideae.764 The distribution of methyl ivorensate- Trichilia, and Aphanamixis, which strongly supported the placing like limonoids with A,B-seco and D carbocyclic rings 601 606 of Nymania in the subfamily Melioideae.283 The chemotaxo- indicated the chemosystematic relevance between the genera nomic link between the genera Nymania and Turraea was Khaya,446,576 and Soymida538 of the subfamily Swietenioideae and established based on the occurrence of nymania-1 (522) in both the genera Dysoxylum,516 and Trichilia520 of the Melioideae. The Nymania capensis and Turraea obtusifolia.509 Three limonoids isolation of 1α,3α-diacetylvilasinin (189) and 1,3-diacetyl-7-tigloyl- from Turraea obtusifolia are structurally similar to hirtin (94) and 12α-hydroxyvilasinin (190)fromMalleastrum antsingyense sup- havanensin (106) and thus represent intermediates or byways on ported the placement of Malleastrum in the subfamily Melioideae the route to the more characteristic prieurianin group, and they although no prieurianin or evodulone-class limonoids were found.244 are consistent with the close taxonomic relationship of Turraea The mexicanolide-class limonoids found in Cipadessa fruticosa617 189 and Nymania. In contrast to the other species of Trichilia, along with the andirobin- and trijugin-class limonoids from C. T. connaroides contains the andirobin, mexicanolide and trijugin cinerascens563,647 provided firm support for including Cipadessa in class limonoids, which could be used as a chemical marker to Trichilieae, which is in agreement with Pennington’sviewpoint.769 differentiate this species from the other species in the same genus.573 Mzikonone (240), the principal limonoid of Turraea robusta, was much less oxidized than the havanensin-class 4. SYNTHESIS OF MELIACEOUS LIMONOIDS limonoids from T. obtusifolia and the prieurianin-class from Because of the important biological activities and the high T. floribunda,189 which suggested that caution needed to be structural complexity, the limonoids of Meliaceae have attracted exercised in defining the oxidation pattern of limonoids as considerable attention from the organic synthesis community, taxonomic markers for the genus Turraea.268 The limonoids which has focused particularly on the total synthesis of the well- from Turraea parvifolia of the Turraeeae tribe were typical of known azadirachtin (292). those from the genera Melia and Azadirachta of the Melioideae The potent antifeedant activity of 292 against various insect which suggests their close chemotaxonomic relationship.243 coupled with its remarkable selectivity and nontoxicicity toward Dysodensiols A-C (1135 1137) from Dysoxylum densiflorum, mammalian organisms made it an attractive candidate as a natural which are likely biotransformed products from a common pesticide. Enormous efforts directed toward the total synthesis of
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Table 19. Structures and Sources of Andirobin-Class Limonoids 556 594
no. compounds substitution groups and others sources
556 andirobin R = O Carapa guianensis;137,437,449,450 Cedrela odorata;533 Swietenia macrophylla445 557 amoorinin R = OH Amoora rohituka534,535 536 558 amoorinin-3-O-α-L-rhamnopyranosyl- R=3-O-α-L-Rha-(1f6)-β-D-Glc Aphanamixis polystachya (1f6)-β-D-glucopyranoside 559 deoxyandirobin R = H; Δ1,2 Soymida febrifuga;537 Khaya grandifoliola164 560 swietmanin J R = OH Swietenia mahagoni458 561 domesticulide A R = H Lansium domesticum100 562 domesticulide B R = Ac L. domesticum100 563 Soymida febrifuga538 564 dihydroamoorinin R = OH Aphanamixis polystachya539 565 aphanamixinin R = O A. polystachya536,540 542 566 astrotrichilin R = cinnamate/nicotinate ester Astrotrichilia asterotricha543 567 cipadonoid B Cipadessa cinerascens544 423,545 530 568 methyl angolensate R1 =O;R2 =R3 =R4 =H Entandrophragma angolense; E. macrophyllum; Guarea thompsonii;475 Soymida febrifuga;537,546 Khaya senegalensis;451,464,547 551 K. anthotheca;552 K. grandifoliola;164,436,553 K. ivorensis;446,447,554 Cedrela odorata;98,168 C. fissilis;132 Lansium domesticum;100 Swietenia mahagoni;112,458,555 Ruagea glabra;556 Carapa guianensis;113,137,437 Cabralea eichleriana;430 Neobeguea mahafalensis;557 Melia azedarach;452 Trichilia catigua;165 Xylocarpus granatum;448 X. moluccensis558 451,467,468,472,547 550,559 552 569 methyl 6-hydroxyangolensate R1 =O;R2 = OH; R3 =R4 =H Khaya senegalensis; K. anthotheca; K. ivorensis;446,447,554 K. grandifoliola;164,436,553,560 Swietenia mahagoni;457,458,555 S. aubrevilleana;445 Lansium domesticum100 100 560,561 570 methyl 6-acetoxyangolensate R1 =O;R2 = OAc; R3 =R4 =H L. domesticum; Khaya grandifoliola; K. senegalensis451,547,549,550,559 α 531 571 methyl 6,12 -diacetoxyangolensate R1 =O;R2 =R3 = OAc; R4 =H Guarea thompsonii 173 572 azecin 1 R1 = OAc; R2 =H;R3 = OAc; Melia azedarach f β R4 = O-L-rha (1 6)- -D-glc 532 573 sandoricin R1 = OAc; R2 =H;R3 = OAc; R4 =OH Sandoricum koetjape 532 574 6-hydroxysandoricin R1 = OAc; R2 =R4 =OH;R3 = OAc S. koetjape α α 562 575 [2 -(2-methylbutanoyl)oxy]sandoricin R1 = -Opiv; R2 = OAc; R3 =OH S. koetjape α α 562 576 [2 -(2-methylpropanoyl)oxy]sandoricin R1 = -OiBu; R2 = OAc; R3 =OH S. koetjape β β β 563 577 methyl 2 ,3 -diacetoxy-3-deoxoangolensate R1 = -OAc; R2 =R3 =H Cipadessa cinerascens β 53 578 cipadesin D R1 =H;R2 = OH; R3 = -OAc C. cinerascens 54 579 cipadesin F R1 = OAc; R2 = OH; R3 =H C. cinerascens α 563 580 cineracipadesin B R1 = OAc; R2 = OH; R3 = -OH C. cinerascens 563 581 cineracipadesin C R1 =H;R2 = OH; R3 =O C. cinerascens α 563 582 cineracipadesin D R1 =R2 =H;R3 = -OAc C. cinerascens α 563,564 583 cineracipadesin E R1 = OAc; R2 = OH; R3 = -OAc C. cinerascens 565,566 584 E.P.1 R1 = OAc; R2 =R3 =H Ekebergia pterophylla 566 585 E.P.2 R1 =H;R2 = Ac; R3 = OAc E. pterophylla 565,566 586 E.P.3 R1 =R3 = OAc; R2 =H E. pterophylla 565 587 E.P.6 R1 = OTig; R2 =H;R3 =OH E. pterophylla 567 588 ekebergin R1 =OiVal; R2 =H;R3 =OAc E. capensis 100 589 domesticulide C R1 = OAc; R2 =O;R3 =OH Lansium domesticum 100 590 domesticulide D R1 = OAc; R2 = OH; R3 =O L. domesticum 568 591 moluccensin N R1 =H;R2 =O;R3 =OH Xylocarpus moluccensis 568 592 moluccensin O R1 =H;R2 = OH; R3 =O X. moluccensis 593 sandoripin A R = Piv Sandoricum koetjape569 594 sandoripin B R = iBu S. koetjape569
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Figure 21. Structures of andirobin-class limonoids 556 594.
Table 20. Other Structures and Sources of Rings B,D-seco Limonoids 595 600
no. compounds substitution groups and others sources
595 methyl 8α-hydroxy-8,30-dihydroangolensate Trichilia connaroides573 596 secomahoganin R = Ac Entandrophragma angolense;545 Swietenia mahagoni;71,111,112 S. macrophylla456 597 deacetylsecomahoganin R = H S. mahagoni457 550,574,575 554 598 khayanoside R = β-D-glucopyranoside Khaya senegalensis; K. ivorensis 599 cedrelanolide I Cedrela salvadorensis570,571 600 swiemahogin A Swietenia mahagoni;572 Khaya ivorensis554
Figure 22. Other structures of rings B,D-seco limonoids 595 600.
292 have been continuing for more than twenty years in several stereogenic centers, seven of which were tetrasubstituted car- research groups. This was undoubtedly due to its complex bon atoms, and a diverse array of oxygenated functionalities in molecular architecture, which comprised sixteen contiguous addition to a rigid conformation imposed by intramolecular
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Table 21. Structures and Sources of Rings A,B,D-seco Limonoids 601 606
no. compounds substitution groups and others sources
601 methyl ivorensate Khaya ivorensis;446,576 Dysoxylum spectabile516 602 Soymida febrifuga538 520 603 elegantin A R1 =O;R2 =OH Trichilia elegans ssp. elegans 520 604 elegantin B R1 = OH; R2 =O T. elegans ssp. elegans α 520 605 1,2-dihydro-l -acetoxyelegantin A R1 =O;R2 =OH T. elegans ssp. elegans α 520 606 1,2-dihydro-l -acetoxyelegantin B R1 = OH; R2 =O T. elegans ssp. elegans
Figure 23. Structures of rings A,B,D-seco limonoids 601 606.
Table 22. Structures and Sources of 1,n-Linkage Rearranged Limonoids 607 625
no. compounds substitution groups and others sources
607 Carapa procera580 608 carapolide B C. procera581 609 carapolide C C. procera;581 C. grandiflora276 fl 276,582 610 carapolide D R1R2 =CH2 C. grandi ora fl 276,582 611 carapolide E R1 =CH3;R2 =OH C. grandi ora 612 carapolide F R = OH C. grandiflora276,582 613 carapolide G R = H C. grandiflora276 α Δ8,9 577,578 614 dukunolide A R1 =R2 = -OH; R3 = H; 5,6-epoxy; Lansium domesticum α 100,577 615 dukunolide B R1 =R2 = -OH; R3 = H; 5,6; 8,9-diepoxy L. domesticum α Δ8,9 100,577 616 dukunolide C R1 =R2 = -OH; R3 = OAc; 5,6-epoxy; L. domesticum α Δ8,9 100,583 617 dukunolide D R1 =R2 = -OH; R3 =H; L. domesticum α 583 618 dukunolide E R1 =R2 = -OH; R3 = H; 8,9-epoxy L. domesticum β 583 619 dukunolide F R1 =R2 = -OH; R3 = H; 8,9-epoxy L. domesticum 620 seco-dukunolide F L. domesticum584 α α β fi 579 621 7 ,12 -diacetoxy-11 -hydroxyneotecleanin R1 = OAc; R2 =H Turraea wake eldii β α fi 579 622 11 ,12 -diacetoxyneotecleanin R1 =O;R2 =Ac T. wake eldii β α β β fi 579 623 11 ,12 -diacetoxy-14 ,15 -epoxyneotecleanin R1 =O;R2 =Ac T. wake eldii α α β β β fi 579 624 7 ,12 -diacetoxy-14 ,15 -epoxy-11 -hydroxyneotecleanin R1 = OAc; R2 =H T. wake eldii 625 11β,12α-diacetoxy-1-deoxo-14β,15β-epoxy-3β- T. wakefieldii579 hydroxy-2-oxo-neotecleanin hydrogen bonding. Furthermore its sensitivity to acid and base approach, which would bring together a decalin fragment with together with its photoinstability made it particularly prone to a hydroxydihydrofuran acetal portion (Scheme 1).771 rearrangement, thereby frustrating many synthesis plans.770 The The strategy in the formation of the decalin unit of 292 strategy applied to the total synthesis of 292, called “relay route” included two different ways. One is the employment of a silyl or “relay synthesis”, consisted of attempting to degrade 292 to a group to control the stereoselectivity of several key steps and to specific potential synthetic intermediate and then transform this introduce C-3 hydroxyl functionality in decalin motif,772 774 and back into the natural product. For example, one application of another is the cleavage of C8 C14 bond via a base-mediated this strategy involved the degradation of the enol double bond to retro-Aldol reaction of natural product 292, in which macrocyclic give an advanced intermediate and development of methods carbonate is a key intermediate.774 776 The degradation of 292 to convert this intermediate back into the natural product by to the demethylated decalin and the subsequent remethylation reintroduction of the enol double bond using an acetal exchange to the protected fragment has been presented. This not only process. In addition, the strategy focused on a convergent connected the total synthesis and the degradation route of 292,
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Figure 24. Structures of 1,n-linkage rearranged limonoids 607 625.
Table 23. Structures and Sources of Mexicanolide-Class Limonoids 626 845
no. compounds substitution groups and others sources
167 587 533,641 626 mexicanolide R1 =R3 =H;R2 =O Carapa procera; Cedrela mexicana; C. odorata; C. fissilis;642 Khaya senagalensis;451,467,603 K. ivorensis;446 K. grandifoliola;164 Neobeguea mahafalensis;557 Cipadessa fruticosa;617,643 Swietenia mahagoni;458 Xylocarpus granatum448 α 467,603 627 2 -hydroxymexicanolide R1 = OH; R2 =O;R3 =H Khaya senegalensis α β 467,468,603 458 628 2 ,3 -dihydroxy-3-deoxymexicanolide R1 =R2 = OH; R3 =H K. senegalensis Swietenia mahagoni β 467,603 644 629 3 -hydroxy-3-deoxymexicanolide R1 =R3 =H;R2 =OH Khaya senegalensis; Cabralea eichleriana 533 164 630 6-hydroxymexicanolide R1 =H;R2 =O;R3 =OH Cedrela odorata; Khaya senegalensis; Lansium domesticum100,645 100 631 6-acetoxymexicanolide R1 =H;R2 =O;R3 = OAc L. domesticum 590 445 632 6-deoxyswietenolide (proceranolide) R1 =R3 =H;R2 =OH Carapa procera; Swietenia macrophylla; S. mahagoni;112 Cedrela odorata;533 Quivisia papinae;646 Xylocarpus granatum448,633 0 0 591 647 633 2 R-methylbutanoylproceranolide R1 =R3 =H;R2 =2R-OPiv Cipadessa baccifera; C. cinerascens 0 0 591 647 634 2 S-methylbutanoylproceranolide R1 =R3 =H;R2 =2S-OPiv C. baccifera; C. cinerascens; Xylocarpus moluccensis558 648 635 proceranolide butanoate R1 =R3 =H;R2 = OBu Khaya ivorensis 458 636 2-hydroxy-3-O-isobutyrylproceranolide R1 = OH; R2 = OiBu; R3 =H Swietenia mahagoni 458 637 2-hydroxy-3-O-benzoylproceranolide R1 = OH; R2 = OBz; R3 =H S. mahagoni 112,603,649 55,445 638 swietenolide R1 =H;R2 =R3 =OH S. mahagoni; S. macrophylla; Khaya grandifoliola;436 Cedrela odorata;510 Quivisia papinae646 α 646 639 2 -hydroxyswietenolide R1 =R2 =R3 =OH Q. papinae 650 640 2-hydroxy-3-O-tigloyl-6-O-acetylswietenolide R1 = OH; R2 = OTig; R3 = OAc Trichilia connaroides
AJ dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 23. Continued no. compounds substitution groups and others sources
613 651 641 2-hydroxy-3-tigloyl-6-deoxyswietenolide R1 = OH; R2 = OTig; R3 =H Capuronianthus mahafalensis; Trichilia connaroides; Swietenia mahagoni458 457,649 642 2-hydroxy-3-O-tigloylswietenolide R1 =R3 = OH; R2 = OTig S. mahagoni 112,652 447 623 643 3-acetylswietenolide R1 =H;R2 = OAc; R3 =OH S. mahagoni; Khaya ivorensis; K. senegalensis 112,603 55,653 644 3-tigloylswietenolide R1 =H;R2 = OTig; R3 =OH Swietenia mahagoni; S. macrophylla 112 445 436 645 6-acetylswietenolide R1 =H;R2 = OH; R3 = OAc S. mahagoni; S. macrophylla; Khaya grandifoliola 112,603 653 646 6-acetyl-3-tigloylswietenolide R1 =H;R2 = OTig; R3 = OAc Swietenia mahagoni; S. macrophylla 55,445,653,654 112,603 647 diacetylswietenolide R1 =H;R2 =R3 = OAc S. macrophylla; S. mahagoni; Khaya ivorensis;446 K. senegalensis623 fi 164,184 601,603,623 648 ssinolide (grandifoliolin, angustinolide, R1 =R3 =H;R2 = OAc K. nyasica; K. senegalensis; 3β-acetoxymexicanolide) K. grandifoliola;602 K. madagascariensis;469 Cedrela fissilis;596 Cabralea eichleriana;430,644 Swietenia mahagoni458 fi 458 164,446 623 649 2-hydroxy ssinolide R1 = OH; R2 = OAc; R3 =H S. mahagoni; Khaya ivorensis; K. senegalensis fi 601,623 650 2,6-dihydroxy ssinolide R1 =R3 = OH; R2 = OAc K. senegalensis β fi 430 98 651 3 -deacetyl ssinolide R1 =R3 =H;R2 =OH Cabralea eichleriana; Cedrela odorata β 641 557 652 khayasin (3 -isobutyryloxymexicanolide) R1 =R3 =H;R2 = OiBu C. odorata; Neobeguea mahafalensis; Cipadessa baccifera;591 Xylocarpus moluccensis;558 Khaya senegalensis;451,655 K. grandifoliola164 164 653 2-hydroxykhayasin R1 = OH; R2 = OiBu; R3 =H K. madagascariensis 451 654 khayasin B R1 =R3 =H;R2 = OBz K. senegalensis 451 617,656 655 khayasin T R1 =R3 =H;R2 = OTig K. senegalensis; Cipadessa fruticosa; C. baccifera;591,657 C. cinerascens;647 Xylocarpus granatum;426,633 X. moluccensis;558 Toona ciliata;290 Swietenia macrophylla;445,653 S. mahagoni112,458 445 656 augustineolide R1 = Tig; R2 = OH; R3 = OAc; R4 = OiBu S. macrophylla 458 657 swietmanin E R1 = Tig; R2 =R4 =H;R3 =OH S. mahagoni 458 623 658 swietmanin F R1 = Ac; R2 =R4 =H;R3 =OH S. mahagoni; Khaya senegalensis 623 659 khayalenoid G R1 = Ac; R2 = OAc; R3 = OH; R4 =H K. senegalensis 623 660 khayalenoid H R1 = Ac; R2 = OAc; R3 =R4 =H K. senegalensis α 623 661 khayalenoid I R1 = Ac; R2 =R3 =R4 =H;11 -OAc K. senegalensis 430 662 cabralin R1 = OAc; R2 =H;R3 =O;R4 =OH Cabralea eichleriana 430 663 isocabralin R1 = OAc; R2 =H;R3 = OH; R4 =O C. eichleriana 100 664 domesticulide E R1 =R3 =O;R2 =R4 =OH Lansium domesticum fi 164 665 2-hydroxy-8(14)-dihydro ssinolide R1 =R2 = OH; R3 =R4 =H Khaya madagascariensis β 469 666 methyl 3 -acetoxy-2-hydroxy-1-oxomeliacate R1 = OH; R2 = OAc; R3 =R4 =H K. madagascariensis 163 164 667 dihydrokhayasin R1 =R3 =R4 =H;R2 = OiBu K. anthotheca; K. madagascariensis β 470,550,559,575,623,658 668 khayanone R1 =H;R2 =O;R3 = OH; R4 = -OH K. senegalensis 604,659 669 xyloccensin N R1 =R3 =H;R2 = OAc; R4 =OH Xylocarpus granatum 605 670 3-deacetylxyloccensin N R1 =R3 =H;R2 =R4 =OH X. granatum 660 671 xylocarpin B R1 =R3 =H;R2 = OTig; R4 =OH X. granatum Δ14,15 545 672 angolensin A R1 =R3 =R4 =H;R2 = OTig; Entandrophragma angolense α 545 673 angolensin C R1 =H;R2 =O;R3 = -OAc; R4 =OH E. angolense β α β 510 674 8 ,14 -dihydroxyswietenolide R1 =R4 =H;R2 = OH; R3 = -OH Cedrela odorata 426 675 granatumin D R1 =R3 =R4 =H;R2 = OTig Xylocarpus granatum 676 3β-hydroxyisomexicanolide Cedrela fissilis642 55,445,612,653,661,662 677 swietenine R1 =H;R2 = OTig; R3 =OH Swietenia macrophylla; S. mahagoni;112,603,663 Khaya ivorensis447 112 678 swietenine B R1 =H;R2 = propanate; R3 =OH Swietenia mahagoni 112 614 434 679 swietenine C R1 =H;R2 = OiBu; R3 =OH S. mahagoni; S. macrophylla; S. humilis 112 680 swietenine D R1 =H;R2 = methacrylyl; R3 =OH S. mahagoni 112 681 swietenine E R1 =H;R2 = OPiv; R3 =OH S. mahagoni
AK dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 23. Continued no. compounds substitution groups and others sources 112 682 swietenine F R1 =H;R2 = OBz; R3 =OH S. mahagoni 112 55,653 683 sweitenine acetate R1 =H;R2 = OTig; R3 = OAc S. mahagoni; S. macrophylla 451,464,467,468 684 6-deoxydestigloylswietenine R1 =R3 =H;R2 =OH Khaya senegalensis (3β-hydroxymexicanolide, Δ8,30) 451,464,466 162 685 6-deoxydestigloylswietenine acetate R1 =R3 =H;R2 = OAc K. senegalensis; Xylocarpus granatum 447 686 3-O-detigloyl-3-O-acetylswietenine R1 =H;R2 = OAc; R3 =OH Khaya ivorensis 603 687 6-acetylswietenine R1 =H;R2 = OTig; R3 = OAc Swietenia mahagoni 630 688 6-O-acetyl-2-hydroxyswietenine R1 = OH; R2 = OTig; R3 = OAc S. mahagoni 559,630,663,664 445 689 2-hydroxyswietenine R1 =R3 = OH; R2 = OTig S. mahagoni; S. macrophylla β 614 613 690 2-hydroxy-6-deoxyswietenine (methyl 3 - R1 = OH; R2 = OTig; R3 =H S. macrophylla; Capuronianthus mahafalensis tigloyloxy-2-hydroxy-1-oxo- meliac-8(30)-enate) 164 691 6-dexoxyswietenine isobutyrate R1 =R3 =H;R2 = OiBu Khaya nyasica 162 692 2-hydroxydestigloyl-6- R1 = OH; R2 = OAc; R3 =H Xylocarpus molluccensis deoxyswientenine acetate β β 451 693 12 -hydroxy-6-deoxy- R1 =R3 =H;R2 = OAc; 12 - OAc Khaya senegalensis destigloylswientenine diacetate 615 98 694 febrifugin (6-desoxyswietenine) R1 =R3 =H;R2 = OTig Soymida febrifuga; Cedrela odorata; Cipadessa baccifera;591,618,657 C. fruticosa;617,643,656 C. cinerascens;647 Toona ciliata;290 Xylocarpus granatum;426 Swietenia mahagoni;603,616 S. macrophylla445,653 434,629,665 695 humilinolide C R1 = OAc; R 2= OTig; R3 =H S. humilis 445 696 6-acetoxyhumilinolide C R1 =R3 = OAc; R2 = OTig S. aubrevilleana 434,629,665 697 humilinolide D R1 = OH; R2 = OAc; R3 = OAc S. humilis 434 698 humilinolide E R1 = OH; R2 = OTig; R3 = OAc S. humilis β 434,619 699 methyl-2-hydroxy-3 -isobutyroxy-1- R1 = OH; R2 = OiBu; R3 =H S. humilis oxomeliac-8(30)-enate β 434 700 methyl-2-hydroxy-3 -tigloyloxy-1- R1 = OH; R2 = OTig; R3 =H S. humilis oxomeliac-8(30)-enate β β 614 701 methyl 3 -tigloyloxy-2,6-dihydroxy-1- R1 = OH; R2 = OTig; R3 = -OH S. macrophylla oxo-meliac-8(30)-enate β 666 184 702 methyl 3 -isobutyryloxy-1-oxomeliac- R1 =R3 =H;R2 = OiBu Carapa procera; Khaya nyasica; 8(30)-enate Cipadessa baccifera591 618,657 617,643,656 703 cipadesin R1 =R3 =H;R2 = OPiv C. baccifera; C. fruticosa 0 0 591 704 2 R-cipadesin R1 =R3 =H;R2 =2R-OPiv C. baccifera 0 0 591 705 2 S-cipadesin R1 =R3 =H;R2 =2S- =OPiv C. baccifera 556 706 ruageanin D R1 = OH; R2 = OAc; R3 =H Ruagea glabra 464 707 6-epidestigloylswietenine diacetate R1 =H;R2 = OAc; R3 = OAc Khaya senegalensis 623 708 khayalenoid E R1 =H;R2 =O;R3 = OAc K. senegalensis α 458 709 swietmanin A R1 =R3 =H;R2 = OiBu; 11 -OAc Swietenia mahagoni α 458 710 swietmanin B R1 =R3 =H;R2 = OAc; 11 -OAc S. mahagoni α 458 711 swietmanin C R1 =R3 =H;R2 = OH; 11 -OAc S. mahagoni α 458 712 swietmanin D R1 =R2 = OAc; R3 =H;11 -OAc S. mahagoni α α α 554 713 11 -acetoxy-2 -hydroxy-6-deoxy- R1 = OH; R2 = OAc; R3 =H; 11 -OAc Khaya ivorensis destigloylswietenine acetate 714 erythrocarpine B R = Bz Chisocheton erythrocarpus667 715 erythrocarpine C R = Cin C. erythrocarpus667 617,656 426,633 716 febrifugin A R1 =O;R2 =OH Cipadessa fruticosa; Xylocarpus granatum 426 717 granatumin E R1 = OH; R2 =H X. granatum 718 dehydrocarapin R = O Cedrela odorata500 719 xylomexicanolide B R = OiBu Xylocarpus moluccensis558 720 mahagonin Swietenia mahagoni668 597 721 angustidienolide R1 =R3 =H;R2 =Ac Cedrela augustifolia
AL dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 23. Continued no. compounds substitution groups and others sources α 597 722 2 -hydroxyangustidienolide R1 = OH; R2 = Ac; R3 =H C. augustifolia 458 472 723 seneganolide A R1 =R2 =R3 =H Swietenia mahagoni; Khaya senegalensis 472 724 2-hydroxyseneganolide A R1 = OH; R2 =R3 =H K. senegalensis 472 725 2-acetoxyseneganolide A R1 = OAc; R2 =R3 =H K. senegalensis 591 426 726 tigloylseneganolide A R1 =R3 =H;R2 = Tig Cipadessa baccifera; Xylocarpus granatum 667 727 erythrocarpine A R1 =R3 =H;R2 =Bz Chisocheton erythrocarpus 426 728 granatumin A R1 =R3 =H;R2 = methylacryl Xylocarpus granatum 426 729 granatumin B R1 =R3 =H;R2 = Piv X. granatum 458 730 swietmanin G R1 = OH; R2 = iBu; R3 =H Swietenia mahagoni 458 731 swietmanin H R1 = OH; R2 = Ac; R3 =H S. mahagoni 458 732 swietmanin I R1 = OH; R2 = Tig; R3 =H S. mahagoni 558 733 xylomexicanolide A R1 =R3 =H;R2 = iBu Xylocarpus moluccensis 623 734 khayalenoid F R1 = OH; R2 = Ac; R3 = S-OAc Khaya senegalensis Δ9,11 646 735 quivisianolide B R1 = OH; R2 = Ang; Quivisia papinae Δ14,15 426 736 granatumin C R1 =H;R2 = Tig; Xylocarpus granatum α 633,639 737 xylogranatin A R1 =R3 =R5 =H;R2 = OTig; R4 = -OH X. granatum α α 669 738 30 -hydroxylxylogranatin A R1 =R3 =H;R2 = OTig; R4 =R5 = -OH X. granatum β 670 739 carapin R1 =R3 =R5 =H;R2 =O;R4 = -H Carapa procera β β 467 545 740 3 -hydroxy-3-deoxycarapin R1 =R3 =R5 =H;R2 = OH; R4 = -H Khaya senegalensis; Entandrophragma angolense β β 184 145 741 methyl-3 -acetoxy-1-oxomeliac-14(15)-enate R1 =R3 =R5 =H;R2 = OAc; R4 = -H Khaya nyasica; Toona ciliata; (3β-acetoxycarapin) Cedrela fissilis132,671 β 672 742 6-hydroxycarapin R1 =R5 =H;R2 =O;R3 = OH; R4 = -H C. glaziovii β β 552 601 743 methyl 3 -acetoxy-6-hydroxy-1-oxomeliac-14- R1 =R5 =H;R2 = OAc; R3 = OH; R4 = -H Khaya anthotheca; K. senegalensis enoate (3β-acetoxy-3-deoxo-6R- hydroxycarapin) α α 458 744 8 -hydroxycarapin R1 =R3 =R5 =H;R2 =O;R4 = -OH Swietenia mahagoni α α 552 745 6R,8 -dihydroxycarapin R1 =R5 =H;R2 =O;R3 =R4 = -OH Khaya anthotheca β β β 445 510 746 3 ,6-dihydroxydihydrocarapin R1 =R5 =H;R2 = OH; R3 = -OH; R4 = -H Swietenia macrophylla; Cedrela odorata β 673 747 xyloccensin X1 R1 =R5 =H;R2 = OH; R3 = -OAc; Xylocarpus granatum α R4 = -OH α 673 748 xyloccensin X2 R1 =R3 =R5 =H;R2 = OH; R4 = -OH X. granatum 491,620,674 749 utilin B R1 = OH; R2 =R5 = OAc; R3 =H; Entandrophragma utile α R4 = -OiBu α 675 750 xylomexicanin B R1 =R3 =R5 =H;R2 = OPiv; R4 = -OH Xylocarpus granatum 751 khayalenoid A R = H; Δ8,9; Δ14,15 Khaya senegalensis622 752 khayalenoid B R = H; Δ8,14 K. senegalensis622 753 khayalenoid C R = OH; Δ8,14 K. senegalensis623 754 khayalenoid D R = H; Δ8,30 K. senegalensis623 α 491,621,674 755 utilin C R1 = -OH; R2 = OAc; R3 =H;R4 = OiBu Entandrophragma utile 625 756 xyloccensin A R1 =R3 =H;R2 =R4 = OiVal Xylocarpus moluccensis α 625 757 xyloccensin D R1 = -OH; R2 =R4 = OiBu; R3 =H X. moluccensis α 624 758 xyloccensin X R1 = -OH; R2 = OPiv; R3 =H;R4 = OiBu X. molluccensis α 624 759 xyloccensin Y R1= -OH; R2= OiBu; R3=H;R4= OPiv X. molluccensis β 633 760 xylocarpin F R1 = -H; R2 =R4 = OAc; R3 =H X. granatum β 633 761 xylocarpin G R1 = -H; R2 = OAc; R3 =H;R4 = OTig X. granatum β 639 762 xylogranatin B R1 = -H; R2 = OTig; R3 =H;R4 = OAc X. granatum β 633,639 763 xylogranatin C R1 = -H; R2 = OPiv; R3 =H;R4 = OAc X. granatum β 639 764 xylogranatin D R1 = -H; R2 = OiBu; R3 =H;R4 = OAc X. granatum β 676 765 xylogranatin S R1 = -H; R2 = OAc; R3 =H;R4 = OPiv X. granatum α 545 766 angolensin B R1 = -OH; R2 = OTig; R3 = OAc; Entandrophragma angolense
R4 = OiBu 625 767 xyloccensin B R1 =R3 =H;R2 =R4 = OiBu Xylocarpus moluccensis 625 768 xyloccensin F R1 = OH; R2 =R4 = OiBu; R3 =H X. moluccensis 626 626 769 xyloccensin I R1 = OH; R2 = OAc; R3 =H;R4 = OPiv X. granatum; X. moluccensis
AM dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 23. Continued no. compounds substitution groups and others sources 626 626 770 xyloccensin J R1 = OH; R2 = OAc; R3 =H;R4 = OiBu X. granatum; X. moluccensis 604,659,677 771 xyloccensin M R1 =R3 =R4 =H;R2 = OAc X. granatum 605 772 3-deacetylxyloccensin M R1 =R3 =R4 =H;R2 =OH X. granatum 660 773 xylocarpin A R1 =R3 =R4 =H;R2 = OTig X. granatum 554 547,550,559,575,678 774 khayalactol R1 =R3 = OH; R2 =O;R4 =H Khaya ivorensis; K. senegalensis 679 775 grandifolide A R1 =R3 = OH; R2 = OAc; R4 =H K. grandifoliola 776 xylocarpin J Xylocarpus granatum677 554 549 551,559 777 seneganolide R1 =R3 =H;R2 =O Khaya ivorensis; K. senegalensis 550,559,658 778 2-hydroxyseneganolide R1 = OH; R2 =O;R3 =H K. senegalensis 679 552 779 anthothecanolide R1 =R2 =R3 =OH K. grandifoliola; K. anthotheca 679 552 780 3-O-acetylanthothecanolide R1 =R3 = OH; R2 = OAc K. grandifoliola; K. anthotheca 552 781 2,3-di-O-acetylanthothecanolide R1 =R2 = OAc; R3 =OH K. anthotheca α α β α 680 782 1 ,8 -oxido-3 -acetoxy-2 - R1 = OOAc; R2 = OAc; R3 =OH K. anthotheca acylperoxy-1α,14α-dihydroxy[3,3,110,2]- bicyclomeliac-7,19-olide 783 3,8-hemiketalcarapin Swietenia mahagoni458 510,681 784 cedrodorin R1 = OH; R2 =R3 =H Cedrela odorata 681 627,628,659 785 6-acetoxycedrodorin R1 = OAc; R2 =R3 =H C. odorata; Xylocarpus granatum α 681 786 6-deoxy-9 -hydroxycedrodorin R1 =R3 =H;R2 =OH Cedrela odorata α 681 787 9 -hydroxycedrodorin R1 =R2 = OH; R3 =H C. odorata 113 510 788 xyloccensin K R1 =R2 =R3 =H C. guianensis; C. odorata; Entandrophragma angolense;545 Xylocarpus granatum448,627,628,633,659,682 628,659 789 xyloccensin W R1 =R2 =H;R3 = OAc X. granatum 790 xyloccensin G R = OPiv X. moluccensis683 683 791 xyloccensin H R1 =H X. moluccensis 426 671 591 792 swietemahonolide R1 =R3 =H;R2 = Tig X. granatum; Cipadessa fruticosa; C. baccifera; C. cinerascens;647 Switenia mahagoni56,112 β 434,629,665,684 614 793 humilinolide A (methyl 3 - R1 =R3 = OH; R2 = iBu S. humilis; S. macrophylla isobutyryloxy-2,6-dihydroxy-8α, 30α-epoxy-1-oxo-meliacate) 434,629,665 794 humilinolide B R1 = OH; R2 = iBu; R3 = OAc S. humilis 434 795 humilinolide F R1 =R3 = OAc; R2 = Tig S. humilis β α α 614 796 methyl 3 -acetoxy-2,6-dihydroxy-8 ,30 - R1 =R3 = OH; R2 =Ac S. macrophylla epoxy-1-oxo- meliacate β α 614,653 630 797 methyl 3 -tigloyloxy-2-hydroxy-8 , R1 = OH; R2 = Tig; R3 =H S. macrophylla; S. mahagoni; 30α-epoxy-1-oxo- meliacate Khaya senegalensis559 (2-hydroxyswietemahonolide) β α α 619 798 methyl 2-hydroxy-3 -isobutyoyl-8 ,30 - R1 = OH; R2 = iBu; R3 =H Swietenia humilis epoxy-1-oxo- meliacate 162,685 556 799 xylocarpin R1 =R3 =H;R2 =Ac Xylocarpus granatum; Ruagea glabra 56,112,652 800 swietemahonin A R1 =H;R2 = propanoyl; R3 =OH Switenia mahagoni 56,112 801 swietemahonin B R1 =H;R2 = propanoyl; R3 = OAc S. mahagoni 56,112 434 802 swietemahonin C R1 =H;R2 = iBu; R3 = OAc S. mahagoni; S. humilis 56,112 803 swietemahonin D R1 =H;R2 = Ac; R3 =OH S. mahagoni 56,112,652 445,653 804 swietemahonin E R1 =H;R2 = Tig; R3 =OH S. mahagoni; S. macrophylla 56,112 55,445 805 8,30-epoxy swietenine acetate R1 =H;R2 = Tig; R3 = OAc S. mahagoni; S. macrophylla (swietemahonin F) 56,112,457,559,630 445 806 swietemahonin G R1 =R3 = OH; R2 = Tig S. mahagoni; S. macrophylla 559,630 653 807 6-O-acetylswietemahonin G R1 = OH; R2 = Tig; R3 = OAc S. mahagoni; S. macrophylla 591 617,647,656 808 ruageanin A R1 =R3 =H;R2 = iBu Cipadessa baccifera; C. fruticosa; Ruagea glabra556 556 809 ruageanin B R1 = OH; R2 = Tig; R3 =H R. glabra 646 810 3-angeloyl-3-detigloylruageanin B R1 = OH; R2 = Ang; R3 =H Quivisia papinae
AN dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 23. Continued no. compounds substitution groups and others sources 556 811 ruageanin C R1 = OH; R2 = Ac; R3 =H Ruagea glabra 434 162 812 humilin B R1 =H;R2 = iBu; R3 =OH Swietenia humilis; Xylocarpus moluccensis 0 0 591 647 813 2 R-cipadesin A R1 =R3 =H;R2 =2R-pivalyoyl Cipadessa baccifera; C. cinerascens 0 0 591 814 2 S-cipadesin A R1 =R3 =H;R2 =2S-pivalyoyl C. baccifera 617,643,656 647 815 cipadesin A R1 =R3 =H;R2 = Piv C. fruticosa; C. cinerascens 563 816 cineracipadesin A R1 =H;R2 = Piv C. cinerascens 646 817 quivisianolide A R1 = OH; R2 = Ang Quivisia papinae 818 quivisianone Q. papinae646 632 819 granaxylocarpin A R1 = OPiv; R2 =Ac Xylocarpus granatum 637 820 xylogranatin B R1 = OTig; R2 =Ac X. granatum Δ2,3 675 821 xylomexicanin A R1 =H;R2 = iBu; X. granatum Δ2,3 632,633 822 granaxylocarpin B (xylocarpin H) R1 =H;R2 = Tig; X. granatum Δ2,3 448,637,638 823 xylogranatin C R1 =H;R2 = Ac; X. granatum 824 ecuadorin Guarea kunthiana686 825 xylocarpanoid A Xylocarpus granatum634 826 xylogranatin E X. granatum687 Δ8,30 Δ14,15 667 827 erythrocarpine D R1 = Cin; R2 =H; , Chisocheton erythrocarpus Δ8,30 667 828 erythrocarpine E R1 = Cin; R2 = OH; C. erythrocarpus 635,636,659 829 xylolactone (xyloccensin L) R1 = Tig; R2 = H; 8,30-epoxy Xylocarpus granatum 632 830 granaxylocarpin C R1 = Tig; R2 = OH; 8,30-epoxy X. granatum 831 grandifolin Khaya grandifoliola561 832 xylogranatin A Xylocarpus granatum637 833 xylogranatin D X. granatum637,638 638 834 xylogranatin I R1 =R2 =H X. granatum 638 835 xylogranatin J R1 =R2 =CH3 X. granatum 638 836 xylogranatin K R1 =H;R2 =CH3 X. granatum 638 837 xylogranatin L R1 =H;R2 =CH2CH3 X. granatum 638 838 xylogranatin M R1 =CH3;R2 =Ac X. granatum 0 638 839 xylogranatin N R1 =H;R2 =2S-methylbutyroyl X. granatum 638 840 xylogranatin O R1 =H;R2 = Tig X. granatum 638 841 xylogranatin P R1 =H;R2 = iBu X. granatum 842 xylogranatin Q X. granatum638 843 xylogranatin R X. granatum638 844 Khaya ivorensis688 845 grandifotane A K. grandifoliola640 but also gave ready access to the demethylated decalin with the of work has been completed on the preparation of models for the hydroxydihydrofuran acetal unit (right-hand side of the molecule decalin portion of 292 and has led to the design of an effective as drawn) and the synthesis of important model compounds.777 route to the fragment methyl (3SR*,3aR*,6aR*,10aR*)-3-hydroxy- Several research groups have proposed the construction of a 5-oxoperhydronaphtho[1,8a-c]furan-3-carboxylate, containing highly functionalized tricyclic trans-decalin system by IMDA some of the functionality required for antifeedant activity.799 A (intramolecular Diels Alder) cycloaddition.778 784 In addition, model substance for 292, 9-hydroxy-dihydrofuro-2,3-tetrahy- the tetracyclic decalin portion was synthesized in an optically dropyran, was synthesized by a route in which the key step pure form via reduction of a silyloxyfuran derivative, and the involved cyclization of hydroxyl-dialdehyde precursors, acetyla- key reactions involved the CBS (Corey-Bakshi-Shibata) asymmetric tion and pyrolysis.800 A tricyclic lactone derived from D-galactal reduction of a ketone and an IMDA reaction.785,786 The development via tin hydride mediated transannular radical cyclization was of a strategy for the functionalization of the decalin portion based on easily converted into an advanced precursor of the tricyclic the thermal Claisen rearrangement represented significant progress dihydrofuran portion of 292.801 The Diels Alder adduct formed toward the total synthesis of 292.787 For a more advanced decalin using Evans’ chiral Cu-bisoxazoline complex catalyst was easily ffi system, both the total synthesis and semisynthesis with e cient and converted to the tricyclic dihydrofuran moiety via SmI2 reductive stereoselective construction of the ABCD rings,788 ABC rings,789 AB cleavage and selective functionalization.802 Furthermore, a synth- rings,790 and B-ring,791 all with full functionality, were reported. esis route to mimics of 292 containing the hydrotetrahydrofur- For biological evaluation and a total synthesis study directed ancarboxylate hemiketal functional moiety was developed.803,804 toward azadirachtin (292), the hydroxyfuran acetal functional group A key tricyclic acetal intermediate has been prepared in optically related to 292 have been prepared792 796 using some reactions pure form in 12 steps from the known (-)-3-endobromotricyclo- which involved an enantioselective route.797,798 An extensive body [3.2.0.02,7]heptan-6-one.805
AO dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
The extreme steric congestion at the C8 C14 bond has intramolecular radical reaction followed by a cation-induced resulted in the failure of many attempted coupling strategies. rupture of an initially formed bridge.811,812 Finally, Ley placed The convergent synthetic approach toward 292 and functional- particular emphasis on the key coupling of a left-hand decalin ized analogs was based on the construction of the C8 C14 bond fragment with a right-hand hydroxydihydrofuran acetal unit via a through a diastereoselective Claisen rearrangement,806 809 or Claisen rearrangement reaction of an intermediate propargylic through a transition metal chemistry strategy,810 or through an enol ether.23
Figure 25. Continued
AP dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Figure 25. Structures of mexicanolide-class limonoids 626 845.
After a long journey of 22 years, the total synthesis of 292 was common intermediate, and the judicious choice of transacetali- finally completed. It could be produced from the key intermedi- zation conditions allowed efficient access to both the azadirachtin ate through a series of selective transformations.770,813 Jauch and the azadirachtinin skeleton (Scheme 2).815 summarized the retrosynthetic analysis, the key Ireland-Claisen The conversion of 292 derivatives to the corresponding rearrangement, radical cyclization, epoxidation, and completion azadirachtinin skeletons could be achieved in high yield under of the total synthesis of 292 through relay synthesis, which mild conditions (Scheme 3).816 Dinitrophenylamino, dansyl, and contained 71 steps with a total yield of 0.00015%, and commen- biotin groups were covalently attached to several derivatives of ted this work was a real highlight of organic chemistry.814 In 292 via a linker group to give fluorescent or immunogenic addition, Devakumar et al. summarized the decalin scaffold compounds that generally retain the biological properties of synthesis, pyran fragment construction, and the ‘last summit’ of 292, which were potential tools for the determination of the the total synthesis of 292, and called it a chemical odyssey.24 mechanisms of 292 in living systems.817 Azadirachtin (292), along with another four limonoids vepaol Some derivatives related to naturally occurring limonoids (303), isovepaol (304), 3-desacetylazadirachtin, and 1-tigloyl-3- were prepared for the purpose of either biological activity acetyl-11-methoxyazadirachtinin (318), was synthesized from a evaluation or reaction mechanistic investigation. On the basis
AQ dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 24. Structures and Sources of Phragmalin-ortho Ester Limonoids 846 962
no. compounds substitution groups and others sources
689 846 phragmalin R1 =R2 =R3 =R4 =R5 =R6 =H Entandrophragma caudatum; Khaya senegalensis559 702 847 12-acetoxyphragmalin R1 =R2 =R3 =R5 =R6 =H;R4 = OAc Chukrasia tabularis 702 848 phragmalin 3,30-di-isobutyrate R1 =R3 =R4 =R5 =H;R2 =R6 = iBu C. tabularis; Entandrophragma caudatum703 162 849 phragmalin 3,30-diacetate R1 =R3 =R4 =R5 =H;R2 =R6 =Ac Xylocarpus moluccensis 162,625 850 xyloccensin E (phragmalin 2,3,30-triacetate) R1 =R2 =R6 = Ac; R3 =R4 =R5 =H X. moluccensis 702 851 12-acetoxyphragmalin 3,30-di-isobutyrate R1 =R3 =R5 =H;R2 =R6 = iBu; R4 = OAc Chukrasia tabularis 702 852 phragmalin 3-isobutyrate 30-propionate R1 =R3 =R4 =R5 =H;R2 = iBu; R6 = propanoyl C. tabularis; Entandrophragma caudatum703 703 702 853 12-acetoxyphragmalin 3- R1 =R3 =R5 =H;R2 = iBu; R4 = OAc; E. caudatum; Chukrasia tabularis
isobutyrate 30-propionate R6 = propanoyl 704 854 leandreanin C R1 =R2 =R6 = Ac; R3 =R4 =H;R5= OAc Neobeguea leandreana 705 855 14,15-dihydroepoxyfebrinin B R1 =R6 = Ac; R2 = epoxytigloyl; R3 =R4 =R5 =H Soymida febrifuga 706 856 tabulalide C R1 =R2 =R6 =H;R3 = OH; R4 =R5 = OAc Chukrasia tabularis 559,706 857 tabulalide D R1 =R6 =H;R2 = Ac; R3 = OH; R4 =R5 = OAc C. tabularis 559 858 2-O-acetyltabulalide D R1 =R2 = Ac; R3 = OH; R4 =R5 = OAc R6 =H C. tabularis 707 859 tabularisin N R1 =H;R2 =R6 = Ac; R3 = OH; R4 =R5 = OAc C. tabularis 708 860 febrinin A R1 = Ac; R2 = Tig; R3 =R4 =R5 =H; Soymida febrifuga Δ14,15 R6 = propanoyl; Δ14,15 708 861 febrinin B R1 =R6 = Ac; R2 = Tig; R3 =R4 =R5 =H; S. febrifuga 705 862 epoxyfebrinin B R1 =R6 = Ac; R2 = epoxytigloyl; S. febrifuga Δ14,15 R3 =R4 =R5 =H; 863 xylocarpin I Xylocarpus granatum633 709 864 neobeguin R1 =R3 =R4 =R5 =H;R2 =R6 = Ac; R7 =CH3 Neobeguea mahafalensis 424,691,693 865 bussein A R1 =R3 =H;R2 = Piv; R4 =R5 = OAc; Entandrophragma bussei
R6 = Ac; R7 =CH3 424,691,693 866 bussein B R1 =R3 =H;R2 = iBu; R4 =R5 = OAc; E. bussei
R6 = Ac; R7 =CH3 693 867 bussein C R1 =R3 =R7 =H;R2 = Piv; R4 =R5 = OAc; R6 =Ac E. bussei 693 868 bussein D R1 =R3 =H;R2 = epoxytigloyl; R4 =R5 = OAc; E. bussei
R6 = Ac; R7 =CH3 693 869 bussein E R1 =R3 =H;R2 = Tig; R4 =R5 = OAc; E. bussei
R6 = Ac; R7 =CH3 693 870 bussein F R1 =R3 =R7 =H;R2 = iBu; R4 =R5 = OAc; R6 =Ac E. bussei 0 693 871 bussein G R1 =R3 =H;R2 =2-hydroxypivalyloyl; E. bussei
R4 =R5 = OAc; R6= Ac; R7=CH3 693 872 bussein H R1 =R3 =H;R2 =R6 = Ac; R4 =R5 = OAc; R7 =CH3 E. bussei 693 873 bussein J R1 =R3 =H;R2 = Piv; R4 = OH; R5 = OAc; E. bussei
R6 = Ac; R7 =CH3 693 874 bussein K R1 =R3 =H;R2 = iBu; R4 = OH; R5 = OAc; E. bussei
R6 = Ac; R7 =CH3 693 875 bussein L R1 =R3 =H;R2 = iBu(OH); R4 =R5 = OAc; E. bussei
R6 = Ac; R7 =CH3 0 0 693 876 bussein M R1 =R3 =H;R2 =2,3 -dihydroxypivalyloyl; E. bussei
R4 =R5 = OAc; R6 = Ac; R7 =CH3 710 877 spicata 2 R1 =R3 =H;R2 = Piv; R4 = OiBu; R5 = OAc; E. spicatum
R6 = Ac; R7 =CH3 707 878 tabularisin P R1 =R4 =R6 =R7 =H;R2 = iBu; Chukrasia tabularis
R3 =R5 = OAc 711 879 chukrasin A R1 =H;R2 = Ac; R3 = OH; R4 = OAc/OiBu; C. tabularis
R5 = OiBu; R6 = Ac/iBu; R7 =CH3 711 880 chukrasin B R1 =R3 =H;R2 = Ac; R4 =R5 = OiBu; C. tabularis
R6 = iBu; R7 =CH3
AR dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 24. Continued no. compounds substitution groups and others sources 711 881 chukrasin C R1 =R3 =H;R2 = Ac; R4 = OAc/OiBu; C. tabularis
R5 = OiBu; R6 = Ac/iBu; R7 =CH3 711 882 chukrasin D R1 =R2 = Ac; R3 =H;R4 = OAc/OiBu; C. tabularis
R5 = OiBu; R6 = Ac/iBu; R7 =CH3 711 883 chukrasin E R1 =R2 = Ac; R3 =H;R4 =R5 = OiBu; C. tabularis
R6 = iBu; R7 =CH3 884 tabularisin O C. tabularis707 704 885 leandreanin A R1 =H;R2 = OAc; R3 =O;R4 =Ac Neobeguea leandreana 704 886 leandreanin B R1 =R4 = Ac; R2 = OAc; R3 =O N. leandreana 443 887 kotschyin B R1 = Ac; R2 =H;R3 = OAc; R4 = iBu Pseudocedrela kotschyii 443 888 kotschyin C R1 = Ac; R2 = OAc; R3 =O;R4 = iBu P. kotschyii 0β 0β 664 456 889 swietenialide D R1 =H;R2 =2 ,3 -epoxytigloyl; R3 = OH; Swietenia mahagoni; S. macrophylla
R4 = propanoyl 0β 0β 456 890 2-acetoxyswietenialide D R1 = Ac; R2 =2 ,3 -epoxytigloyl; R3 = OH; S. macrophylla
R4 = propanoyl 0β 0β 456 891 2,11-diacetoxyswietenialide D R1 = Ac; R2 =2 ,3 -epoxytigloyl; R3 = OAc; S. macrophylla
R4 = propanoyl 0β 0β 456 892 11-deoxyswietenialide D R1 =R3 =H;R2 =2 ,3 -epoxytigloyl; S. macrophylla
R4 = propanoyl 0β 0β 456 893 swietenitin G R1 =R4 = Ac; R2 =2 ,3 -epoxytigloyl; R3 =OH S. macrophylla 456 894 swietenitin H R1 = Ac; R2 = Tig; R3 = OAc; R4 = propanoyl S. macrophylla 895 swietenialide E S. mahagoni664 443 896 kotschyin A R1 =R2 = Ac; R3 = iBu Pseudocedrela kotschyii 0β 0β 456 897 swietenitin A R1 =R3 = Ac; R2 =2 ,3 -epoxytigloyl S. macrophylla 0α 0α 456 898 swietenitin B R1 =R3 = Ac; R2 =2 ,3 -epoxytigloyl S. macrophylla 0β 0β 456 899 swietenitin C R1 = Ac; R2 =2 ,3 -epoxytigloyl; S. macrophylla
R3 = propanoyl 0β 0β 456 900 swietenitin D R1 =H;R2 =2 ,3 -epoxytigloyl; S. macrophylla
R3 = propanoyl 456 901 swietenitin E R1 = Ac; R2 = Tig; R3 = propanoyl S. macrophylla 456 902 swietenitin F R1 =H;R2 = Tig; R3 = iBu S. macrophylla 903 pseudrelone B Pseudocedrela kotschyii694 696 904 chukvelutilide A R1 =R2 =H Chukrasia tabularis 696 905 chukvelutilide B R1 = Ac; R2 =H C. tabularis 696 906 chukvelutilide C R1 =H;R2 =CH3 C. tabularis 696 907 chukvelutilide D R1 = Ac; R2 =CH3 C. tabularis 696 908 chukvelutilide E R1 =R2 = Ac; R3 =H C. tabularis 696 909 chukvelutilide F R1 =H;R2 = iBu; R3 =CH3 C. tabularis 910 chuktabrin B C. tabularis697 707,712,713 911 tabularisin A R1 = OAc; R2 =Ac C. tabularis 707,712,713 912 tabularisin B R1 = OAc; R2 =H C. tabularis 707,712 913 tabularisin E R1 =H;R2 =Ac C. tabularis 707,712 914 tabularisin F R1 =R2 =H C. tabularis 707 915 tabularisin J R1 = OH; R2 =Ac C. tabularis 707 916 tabularisin K R1 = OH; R2 =H C. tabularis 530 714 917 candollein R1 =H;R2 = iBu Entandrophragma candollei; E. cylindricum β 714 918 -dihydroentandrophragmin R1 = OH; R2 = iBu E. cylindricum 919 entandrophragmin R = iBu E. cylindricum;168,423,530,714 E. bussei;424,530 E. spicatum;530,710 E. caudatum530 920 utilin R = Ac E. utile168,423,530 664 921 swietenialide A R1 =H;R2 = Tig; R3 =CH3 Swietenia mahagoni 664 922 swietenialide B R1 =H;R2 = Tig; R3 =CH2CH3 S. mahagoni 0β 0β 664 923 swietenialide C R1 =H;R2 =2 ,3 -epoxytigloyl; R3 =CH3 S. mahagoni 0β 0β 456 924 swietenitin I R1 =H;R2 =2 ,3 -epoxytigloyl; S. macrophylla
R3 =CH2CH3
AS dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 24. Continued no. compounds substitution groups and others sources 0β 0β 456 925 swietenitin J R1 = Ac; R2 =2 ,3 -epoxytigloyl; S. macrophylla
R3 =CH2CH3 456 926 swietenitin K R1 = Ac; R2 = Tig; R3 =CH2CH3 S. macrophylla 580,715 927 procerin R1 = propanoyl; R2 =H;R3 = OAc; R4 =Ac Carapa procera 0β 0β 456 928 swietenitin L R1 =2 ,3 -epoxytigloyl; R2 = OH; Swietenia macrophylla
R3 =H;R4 = proanoyl 0β 0β 456 929 swietenitin M R1 =2 ,3 -epoxytigloyl; R2 = OAc; S. macrophylla
R3 =H;R4 = proanoyl 930 febrinolide Soymida febrifuga705 457 931 swietephragmin A R1 = Ac; R2 = Tig; R3 =R4 =H;R5 = CH(CH3)2 Swietenia mahagoni 457 932 swietephragmin B R1 = Ac; R2 = Tig; R3 =R4 =H; S. mahagoni
R5 = CH(CH3)CH2CH3 457 933 swietephragmin C R1 =R3 =R4 =H;R2 = Tig; R5 = S. mahagoni
CH(CH3)CH2CH3 α 716 934 12 -acetoxyswietephragmin C R1 =R3 =H;R2 = Tig; R4 = OAc; S. macrophylla
R5 = CH(CH3)CH2CH3 β β α 716 935 3 -O-destigloyl-3 -O-benzoyl-12 - R1 =R3 =H;R2 = Bz; R4 = OAc; S. macrophylla
acetoxyswietephragmin C R5 = CH(CH3)CH2CH3 457 936 swietephragmin D R1 =R3 =R4 =H;R2 = Tig; R5 = CH(CH3)2 S. mahagoni α 716 937 12 -acetoxyswietephragmin D R1 =R3 =H;R2 = Tig; R4 = OAc; S. macrophylla
R5 = CH(CH3)2 β β α 716 938 3 -O-destigloyl-3 -O-benzoyl-12 - R1 =R3 =H;R2 = Bz; R4 = OAc; R5 = CH(CH3)2 S. macrophylla acetoxyswietephragmin D 457 939 swietephragmin E R1 =R4 =H;R2 = Tig; R3 = OH; S. mahagoni
R5 = CH(CH3)CH2CH3 716 940 6-O-acetylswietephragmin E R1 =R4 =H;R2 = Tig; R3 = OAc; S. macrophylla
R5 = CH(CH3)CH2CH3 β β 716 941 3 -O-destigloyl-3 -O-benzoyl-6-O- R1 =R4 =H;R2 = Bz; R3 = OAc; S. macrophylla
acetylswietephragmin E R5 = CH(CH3)CH2CH3 0 653 942 6-O-acetyl-3 -demethylswietenphragmin E R1 =R4 =H;R2 = Tig; R3 = OAc; S. macrophylla
R5 = CH(CH3)2 457 943 swietephragmin F R1 =R3 =R4 =H;R2 = Tig; R5 =CH2CH3 S. mahagoni 457 944 swietephragmin G R1 =R3 =R4 =H;R2 = Tig; R5 =CH3 S. mahagoni 717 945 swietephragmin H R1 = Ac; R2 = Tig; R3 =R4 =H;R5 =CH2CH3 S. macrophylla 717 946 swietephragmin I R1 = Ac; R2 = Tig; R3 =R4 =H;R5 =CH3 S. macrophylla 717 947 swietephragmin J R1 = Ac; R2 = Tig; R3 =H;R4 = OH; R5 =CH2CH3 S. macrophylla 448,659,699,718 948 xyloccensin O R1 =H;R2 = OAc Xylocarpus granatum 448,633,639,659,699,718 949 xyloccensin P R1 =R2 = OAc X. granatum 639,659,700,701,718 950 xyloccensin Q (xyloccensin R) R1 = OH; R2 = OAc X. granatum 659,700,701 951 xyloccensin R (xyloccensin Q) R1 =R2 =OH X. granatum 659,700,701 952 xyloccensin S R1 = OAc; R2 =OH X. granatum 659,700 953 xyloccensin T R1 =H;R2 =OH X. granatum 659,700 954 xyloccensin U R1 = OH; R2 =H X. granatum 659,700,701 955 xyloccensin V (xyloccensin T) R1 = OAc; R2 =H X. granatum 707,712,713 956 tabularisin C R1 = OAc; R2 =H;R3 =R4 =Ac Chukrasia tabularis 713 957 tabularisin D R1 =R2 =R4 =H;R3 =Ac C. tabularis 707,712 958 tabularisin G R1 =R2 =H;R3 =R4 =Ac C. tabularis 707,712 959 tabularisin H R1 = OAc; R2 =H;R3 = Ac; R4 = iBu C. tabularis 707,712 960 tabularisin I R1 = OAc; R2 =R3 =H;R4 = iBu C. tabularis 707 961 tabularisin L R1 = OAc; R2 =R3 =H;R4 =Ac C. tabularis 707 962 tabularisin M R1 = OAc; R2 =R4 = Ac; R3 =H C. tabularis of an intramolecular cyclopropanation of a diazo ketone and sub- synthesis of a model compound for azadiradione (12) was accom- sequent selective cleavage of a cyclopropyl ketone, a stereoselective plished starting from α-cyclocitral in 12 steps with 15% overall
AT dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW yield.818 Early in 1989, Corey reported the synthesis of 12 from and nature of the substituent seemed to be crucial for the cytotoxic trans,trans-farnesol stereoselectively.819 Sastry et al. prepared a activity.820 The brief and stereoselective synthesis of havanensin- series of nimbolide (345) derivatives modified on the lactone ring class limonoid models was based on a radical domino reaction under catalyst-free conditions, and pointed out that the position converting an epoxyketone to a bicyclic hydroxyketone, and was
Figure 26. Continued
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Figure 26. Structures of phragmalin-ortho ester limonoids 846 962. achieved in six steps overall from simple cyclohexenones Besides chemical conversion, structural modification using (Scheme 4).821 biocatalysts was also documented. Nocardia sp. quantitatively A possible key intermediate in the biosynthesis of the ring converted salannin (332) and 3-deacetylsalannin (333) into D-seco limonoids was synthesized by the conversion of the side- 3-deacetoxy-1-de[(E)-2-methylbut-2-enoloxy]salannin-1-en-3-one, chain of turraeanthin, a protolimonoid in Turraeanthus africanus, a potentially bioactive compound with an α,β-unsaturated into a β-substituted furan in two steps with considerable yield.822,823 ketone moiety in ring A.838 The tactics of the synthesis of fraxinellone (1142) included reac- tion of 6-formyl-2,6-dimethyl-cyclohex-2-enecarboxylates with furyl- lithium followed by double-bond isomerization with base,824,825 5. BIOLOGICAL ACTIVITIES OF MELIACEOUS and conversion from fraxinellonone (1141) in short steps.826 LIMONOIDS After formation of the five-membered lactone, an aldol reaction Meliaceous limonoids have been gaining global acceptance in and olefin metathesis established the bicyclic ring system, in agricultural applications and in contemporary medicine for their which the catalytic diastereoselective Oshima Utimoto reaction myriad but discrete properties. The need to protect our food was employed as key step (Scheme 5).827 The short and stereo- supply from phytophagous insect attack using ecologically controlled simple synthetic approach to the limonoids system acceptable methods has led to a growing interest in behavior was presented in 1987 by Corey et al., which introduced a high modifying chemicals from natural sources. For example, con- susceptibility for α-oxygenated, α-stannylated allylic systems to sidering azadirachtin (292), we see that its potent activity against undergo free radical attack at the γ-carbon.828 a broad range of insect species combined with its remarkable Chemical transformation was considered to be an efficient nontoxicity toward mammalian organism made 292 an attractive method in structure elucidation and revision. A direct relation- candidate as a natural pesticide.839 Miscellaneous activities of ship between the melianes and meliacins (limonoids) was meliaceous limonoids have been investigated and some wonder- established through opening the 7α,8α-epoxide ring of a melia- ful general reviews,840 842 and specific reviews on insect growth none derivative.829 Swietenine (677) was converted into diace- regulating activity,843 insecticidal activity,34,844 and the cytotoxic tylswietenolide (647), two compouds which differed mainly in activity against the P388 cell line845 have been presented in the the position of the double bond, in seven steps via 14α-hydroxy- past decades. In addition, the biological activities of limonoids swietenine and the Δ8,30, Δ14,15 diene intermediates.830 from Melia azedarach,37,44 47 M. toosendan,47,85 and Azadir- Khayanthone (111) was converted into khivorin (434) by oxidation achta indica,3,29,35 37,39,41 43,846 including especially the acti- with alkaline hydrogen peroxide followed by reacetylation.831 vities19,26 28,30,847 and commercial application of 292,848 have The preparations of methyl angolensate (568) and andirobin been reviewed. Furthermore, the modes and toxicity characteristics (556) from 7-deacetoxy-7-oxokhivorin (441)529 substantiated of the biological action of 292 were presented.32,33 For example, the suggestion that the characteristic bicycle[3.3.1]nonane ring Mordue et al. proved that the mode of 292 involved (i) effects on system of the swietenine group was formed from the normal deterrent and other chemoreceptors resulting in antifeedancy (ii) tetracyclic triterpene nucleus by oxidative cleavage of ring B effects on ecdysteroid and juvenile hormone titers through a followed by intramolecular Michael addition of a C-2 carbanion blockage of morphogenetic peptide hormone release, and (iii) direct to the diene lactone system.609 Mexicanolide (626) was prepared effects on most other tissues studied resulting in an overall loss of from 7-deacetoxy-7-oxokhivorin (441) via a diene-lactone inter- fitness of the insect.25 The biological activity of ring D and rings B,D- mediate, which subsequently underwent intramolecular Michael seco limonoids of Meliaceae,50 and of gedunin (416)havealsobeen addition by alkaline hydrolysis.832 834 E.P.1 (584) has been summarized recently.49 Furthermore, the activities of natural limo- partially synthesized from gedunin (416), by a synthesis in which noids from plants have been presented including the meliaceous the key stage involved the Baeyer Villiger oxidation of the 7-oxo limonoids as one of their discussion topics.10,16 18 group to a lactone.835 416 was transformed along an unam- In addition, the toxicity evaluation of meliaceous limonoids biguous route into 6β-hydroxygedunin (420) and the chemical has been reported occasionally. Among the six limonoids from and spectroscopy properties of the acetate of this product were Melia azedarach,azedarachinB(160) showed remarkable BST ff α 836 di erent from the natural 6 -acetoxygedunin (418). An (brine shrimp lethality test) activity with an LC50 value of investigation was made of the oxidation of 626 and related 0.0098 μM.218 1-Methacrylyl-3-acetyl-11-methoxymeliacarpi- fi compounds with a view to the partial preparation of the 1,8- nin (326) exhibited signi cant lethal activity with an IC50 value hemiacetal bridge characteristic of the limonoids such as of 19 μg/mL in the BST test.346 The highest dose of azadir- xyloccensin A (756) which originated from Xylocarpus achtin (292), 1500 mg/kg, was well tolerated by rats of both molccensis.837 sexes thus could be used as a basal dose for the determination of the
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Figure 27. Structures of polyoxyphragmalin limonoids 963 1015.
NOEL (no-observed-effect level) of 292 to calculate its safety ichthyotoxic activity at a concentration of 50 ppm, while fraxinellone margin.849 Nimbolide (345) was proved to be toxic to mice only (1142)requiredonly10ppm.230 when given i.p. and i.v., and less toxic to rats and hamsters, and it was supposed that when given i.v., the possible cause of death induced 5.1. Biological Activities in Agricultural Use by it was a sudden hypotensive shock.850 Azedaralide (1138), 5.1.1. Insects Antifeeding Activity. Insect antifeedant acti- fraxinellonone (1141)and12α-acetoxyfraxinellone (1147)showed vity, the most potent activity of limonoids, has been extensively
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Table 25. Structures and Sources of Polyoxyphragmalin Limonoids 963 1015
no. compounds substitution groups and others sources
723 963 moluccensin H R1 =R2 =H;R3 =Ac Xylocarpus moluccensis 568 964 moluccensin H R1 = Piv; R2 =H;R3 = iBu X. moluccensis 568 965 moluccensin I R1 = iBu; R2 =H;R3 = Piv X. moluccensis 568 966 moluccensin J R1 = Piv; R2 = iBu; R3 =H X. moluccensis 723 967 moluccensin I R1 =H;R2 = OCH3;R3 =Ac X. moluccensis 723 968 moluccensin J R1 =R2 =H;R3 =Ac X. moluccensis 568 969 moluccensin K R1 =H;R2 = Piv; R3 = iBu X. moluccensis 568 970 moluccensin L R1 =R3 = Piv; R2 =H X. moluccensis 971 tabularin Chukrasia tabularis724 669 972 xylogranatin E2 Xylocarpus granatum Δ14,15 706 973 tabulalin R1 =R3 = OH; R2 = Ac; R4=H; Chukrasia tabularis 719,725 974 atomasin A R1 = OAc; R2 = Ac; R3 =H;R4= iBu Entandrophragma candollei 719,725 975 atomasin B R1 = OAc; R2 = Ac; R3 =H;R4= propanoyl E. candollei 717 976 swietemacrophine R1 = OH; R2 =R4= Tig; R3 = OAc Swietenia macrophylla 977 xylocarpin K Xylocarpus granatum677 978 tabulalide E Chukrasia tabularis706 979 granatumin F R = H Xylocarpus granatum426 980 granatumin G R = OH X. granatum426 632,633 981 xylocarpin A (granaxylocarpin E) R1 = Ac; R2 = OAc; R3 =R4 =R5 =H X. granatum 633 982 xylocarpin B R1 = Ac; R2 =R3 =R4 =R5 =H X. granatum 633 983 xylocarpin C R1 =R2 =R3 =R5 =H;R4 = OAc X. granatum 632,633 984 xylocarpin D (granaxylocarpin D) R1 = Ac; R2 = OH; R3 =R5 =H;R4 = OAc X. granatum 633 985 xylocarpin E R1 = Ac; R2 = OAc; R3 =R5 =H;R4 =OH X. granatum investigated with respect to many kinds of insects. For example, a Using Pericallia ricini in dual choice bioassay, nymania 3 (478) number of evaluations of the well-known azadirachtin (292)were was an effective antifeedant at concentrations of 1 10 μg/cm2 carried out, and some nice reviews described its antifeedancy leaf, which is half as active as 292.497 Salannin (332) was less against miscellaneous insects in detail.25 27 In addition, some active than 292 in feeding suppression against the larvae of antifeeding data of 292 are summarized in Table 32. With as l Spodoptera littoralis and Earias insulana.857 292 was more potent ittle as 0.2 ppm of 292 incorporated into the diet of Spodoptera as an antifeedant and growth inhibitor than any of five limonoids frugiperda, it showed antifeedant effects on first instar larvae and 17β-hydroxyazadiradione (18), salannin (332), 6-deacetylnim- inhibited the molting of the nymphs to the adult stage when it was bin (392), gedunin (416), and 7-deacetylgedunin (421) against applied topically with 0.01 μg to newly molted fifth instar nymphs Helicoverpa armigera,858 and produced almost 100% larval mor- of Oncopeltus fasciatus.851 292 also elicited dose-dependent neural tality at 1 ppm concentration.859 At 4 μg/cm2 and 1 μg/cm2, the and antifeedant behavioral responses in S. littoralis, Schistocerca isomeric mixture of meliartenin (164) was active as 292 in gregaria,andLocusta migratoria when it was used to investigate the strongly inhibiting the larval feeding of Epilachna paenulata mechanism of its effects on the feeding behavior of these three and S. eridania.208 1-Tigloyl-3-acetylazadirachtol (297) and species.26 The pathological effects of 292 on S. gregaria and marrangin (1067) were reported as being more potent than L. migratoria were closely linked to a loss of feeding, with injections 292 in the 24 h dual choice antifeedant test against E. varivestis of 5, 10, and 15 μg/g causing an increasingly rapid onset of the (Table 33).322 Similarly, the crop protection against Schistocerca effects associated with an increasingly reduced food intake.852 In gregaria afforded by 292 resulted from both antifeedancy and greenhouse and seedbed tests, the feeding deterrence provided by toxicity, whereas 3-tigloylazadirachtol (296) was more effective 292 against the striped Acalymma vittatum was not as great as by by direct toxicity after significant ingestion.860 Cnaphalocrocis carbaryl.853 Exposure of 292 to sunlight caused a rapid decrease in medinalis larvae which were chronically exposed to any of 17β- antifeedant potency against newly emerged first-instar (0.046 mg) hydroxyazadiradione (18), 292, salannin (332), deacetylnimbin of Spodoptera frugiperda, and acetone solutions of 292 exposed for (392), gedunin (416), or 7-deacetylgedunin (421), showed a seven days gave more than a 50% reduction in activity.854 Inter- reduction in weight of 59 89% and exhibited a significant estingly, Crocidolomia binotalis was capable of detoxifying the reduction in activities of acid phosphatases (ACP), alkaline antifeedancy of 292 to a limited extent at the cost of poor weight phosphatases (ALP), and adenosine triphosphatases (ATPase). gain and disruption in larval and pupal development.855 Feeding These results indicate that neem limonoids affected gut enzyme behavior of four slug species of Deroceras reticulatum, Arion activities.861,862 distinctus, Agriolimax caruanae,andMaximus sp., as detected by The five limonoids 17β-hydroxyazadiradione (18), salannin the amount of leaf eaten compared to the controls, was (332), 6-deacetylnimbin (392), gedunin (416), and 7-deacetyl- not affected by the presence of 292 at those concentrations gedunin (421)affected feeding, development and reproduction (<500 ppm) which deterred from feeding in Rhopalosiphum padi in Helicoverpa armigera, and the reduced nutritional efficiency and Sitobion avenae.856 and fecundity were recorded as the consequence of postingested
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Table 26. Structures and Sources of 8,11-Linkage Limonoids (Trijugin-Class) 1016 1043
no. compounds substitution groups and others sources β 729 1016 trijugin A R1 =H;R2 =O;R3 = -OH; R4 = OAc Heynea trijuga β 573 1017 trijugin G R1 =O;R2 = OPiv; R3 = -OH; R4 =H Trichilia connaroides α 733 1018 voamatin A R1 = OH; R2 = OCin; R3 = -OH; R4 =H Astrotrichilia voamatata β 733 1019 voamatin B R1 = OH; R2 = OCin; R3 = -OH; R4 =H A. voamatata 1020 trijugin B R = H Heynea trijuga729 1021 trijugin B acetate R = Ac H. trijuga734 730 1022 capensolactone 3 R1/R2 = ONic/OiBu; R3 =H;R4 =R5 = OAc Ekebergia capensis 544,735 1023 cipatrijugin A R1 =R3 =R4 =R5 =H;R2 = OAc Cipadessa cinerascens 563,735 1024 cipatrijugin B R1 =R4 =R5 =H;R2 = OAc; R3 =OH C. cinerascens 563,735 1025 cipatrijugin C R1 =R4 =R5 =H;R2 =R3 = OAc C. cinerascens 563,735 1026 cipatrijugin D R1 =R3 =R5 =H;R2 =R4 = OAc C. cinerascens 736,737 1027 sandrapin A R1 =R2 =R5 = OAc; R3 =H;R4 =OH Sandoricum koetjape 736,737 1028 sandrapin B R1 = OPiv; R2 =R5 = OAc; R3 =H;R4 =OH S. koetjape 736,737 1029 sandrapin C R1 = OiBu; R2 =R5 = OAc; R3 =H;R4 =OH S. koetjape 737,738 1030 sandrapin D R1 = OTig; R2 =R5 = OAc; R3 =H;R4=OH S. koetjape 737,738 1031 sandrapin E R1 = methacrylate; R2 =R5 = OAc; R3 =H;R4 =OH S. koetjape 565 1032 E.P.4 R1 =R4 = OAc; R2 = OAng; R3 =R5 =H Ekebergia pterophylla 730 1033 capensolactone 1 R1 = iBu; R2 =R4 =H;R3 =OH E. capensis 730 1034 capensolactone 2 R1/R2 = Nic/Piv; R3 = OH; R4 =Ac E. capensis 565 1035 E.P.5 R1 =R2 =R4 = Ac; R3 =H E. pterophylla 1036 trichilin A Trichilia connaroides731 1037 trijugin H T. connaroides573 54,544,564 1038 cipadesin D R1 =R3 =H;R2 = OAc Cipadessa cinerascens 54,563 1039 cipadesin E R1 = OH; R2 =R3 =H C. cinerascens 563 1040 cineracipadesin F R1 = OAc; R2 =R3 =H C. cinerascens 564 1041 cipadesin H R1 =R2 =R3 =H C. cinerascens 564 1042 cipadesin I R1 =H;R2 =R3 = OAc C. cinerascens 1043 trichilin B Trichilia connaroides731
Figure 28. Structures of 8,11-linkage limonoids (trijugin-class) 1016 1043.
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Table 27. Structures and Sources of 10,11-Linkage Limonoids (Cipadesin-Class) 1044 1053
no. compounds substitution groups and others sources
564,631 1044 cipadesin C R1 = OAc; R2 =H;R3 =OH Cipadessa cinerascens 53 1045 cipadesin E R1 =R2 =H;R3 =OH C. cinerascens 544 1046 cipadonoid C R1 =R2 =R3 =H C. cinerascens 544 1047 cipadonoid D R1 =R2 =H;R3 = OAc C. cinerascens 544 1048 cipadonoid E R1 =H;R2 =R3 = OAc C. cinerascens α 544 1049 cipadonoid F R1 =H;R2 = OAc; R3 = -CH3 C. cinerascens α α 544 1050 cipadonoid G R1 =H;R2 = OAc; R3 = -CH3;11 -OH C. cinerascens β 563,631,735 1051 cipadesin A R1 =R2 = OAc; R3 = -CH3 C. cinerascens β 631 563,564,671 1052 cipadesin B R1 = OAc; R2 =H;R3 = -CH3 C. cinerascens; C. fruticosa β 564 1053 cipadesin G R1 =R2 =H;R3 = -CH3 C. cinerascens
Table 28. Sources of Rearranged Limonoids with Other Linkage 1054 1062
no. compounds sources
1054 walsuronoid A Walsura robusta739 1055 4α,6α-dihydroxy-A-homoazadirone Azadirachta indica742 1056 spirosendan Melia toosendan85,247,743 1057 volkensinin M. volkensii744 1058 walsuronoid B Walsura robusta739 1059 walsuronoid C W. robusta739 Figure 29. Structures of 10,11-linkage limonoids (cipadesin-class) 1060 delevoyin C Entandrophragma delevoyi425 1044 1053. 740,741 1061 cipadonoid A Cipadessa cinerascens 1062 cumindysoside B Dysoxylum cumingianum745 toxic effects of these compounds.863 Both azecins 1 and 3 (572 and 101) were effective antifeedants when incorporated into lateral sensillum styloconicum.864,865 In other experiments, when the fourth-instar larvae of Spodoptera litura and third-instar larvae Pieris brassicae fed on its natural foodplant, the deterrent effect of of Henosepilachna vigintioctopunctata, as was evidenced by the 167 and salannin (332) were mediated solely via the medial reduced growth rate, increased time of pupation, and even deterrent receptor, whereas inhibitory effects on the sugar and significant mortality.173 Of the five limonoids 94 98 from glucosinolate receptors did not play a significant role.866 Inves- Trichilia pallida, methyl 6,11β-dihydroxy-12α-(2-methylpro- tigation of the bioefficacy and mode of action of some salannin- panoyloxy)-3,7-dioxo-14β,15β-epoxy-1,5-meliacadien-29-oate class limonoids and their role in a multicomponent system (97) showed the greatest activity in tests against the larvae of against lepidopteran larvae led to the conclusion that nonazadir- S. littoralis, S. exigua, Heliothis virescens, and Helicoverpa armigera achtin limonoids having structural similarities and explicitly with feeding index (FI) values varing from 40 to 49.171 In the similar modes of action have no potentiating effect in any antifeeding percentage test against S. littoralis, khayalactol (774) combination.366 Ortego et al. concluded that the effects of showed the highest potential with 83.8% at 1000 μg/mL, azadirone (1) and the mixture of 3,7-di-O-acetylhavanensin followed by 1-O-acetylkhayanolide A (1003) with 58.3% at (107) and 1,7-di-O-acetylhavanensin (108) on digestive pro- 500 μg/mL, khayanolide D (1006) with 55.8 at 200 μg/mL teases and detoxication enzymes in the larval midgut of Leptino- and finally 1003 with 31.4% at 100 μg/mL.550 The growth tarsa decemlineata larvae reflected their postulated mode of inhibitory activities after 7 days and antifeedant activities of 774, action.867 Salannin (332) and nimbinene (1099) showed no khayanolide A (1002), khayanolide B (1004), and 1-O-acetyl- toxicity-mediated effects on Spodoptera litura larvae, and the khayanolide B (1005) were evaluated against S. littoralis. Among antifeedant activity was a result of the effects on other chemo- 868 these, 1004 was the most active antifeedant with an EC50 value of receptors. Potentiation among nonazadirachtin limonoids 6.96 mg/kg for growth inhibitory activity and 2.19 mg/kg for having two explicitly different modes of action, such as feeding antifeedancy.678 Xylogranatins F, G, and R (1156, 1157, and deterrence and physiological toxicity, might be playing a signi- 843) exhibited marked antifeedant activity against the third-instar ficant role in the potentiation effect.442 larvae of Mythimnaseparate at a concentration of 1 mg/mL. Among From studies in which the Spodoptera species insects were ff these, 1157 was the most potent with AFC50 (concentration for frequently used, the EC50 (50% e ective concentration), ED50 50% antifeedant activity) values of 0.31 and 0.30 mg/mL at expo- (50% effective dosage), MAC (minimum antifeedant con- 638 sure times of 24 and 48 h, respectively. centration), PC50 (50% protective concentration), PC95 (95% Modes of action other than their useful antifeedant activity protective concentration), AR (antifeedant rate), FI50 (50% were also investigated for limonoids. Chuanliansu (167) stimu- feeding inhibition), and AI (antifeedant index, mean ( SEM) lated a deterrent receptor cell located in the medical maxillary values of antifeedant activity of meliaceous limonoids were sensillum styloconicum, and inhibited responses of both the summarized in detail (Tables 33 and 34). Unfortunately, some sugar and glucosinolate receptor cell which are localized in the limonoids were declared to show antifeedant activity against
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Figure 30. Structures of rearranged limonoids with other linkages 1054 1062. different insects, but no data had been presented in the original concentration of 200 400 ppm, followed by nimbolidins at paper. These limonoids were 7-acetyltrichilin A (136),200 1α,3α- 500 ppm and trichilinins at 1000 ppm.239 diacetylvilasinin (189),245 toonacilin (268) and 6-acetoxytoonacilin Ley et al. pointed out that the potent antifeedant activity of the (269),286,289 21-(R,S)-hydroxytoonacilide (279) and 23-(R,S)- derivatives of azadirachtin (292) with C-7 β-OH were signifi- hydroxytoonacilide (280),288 salannin (332),853 3-deacetylsalannin cantly less active than its α-epimer.871 Mordue et al. proposed (333)andsalannol(336),245 20,30-dehydrosalannol (338),349 that the C-7, C-11, C-22, and C-23 positions of the carbon ring munronins A E(498 500, 1151, 1116),506 methyl 3β-iso- were key positions for bioactivity where substitution significantly butyrloxy-1-oxomeliac-8(30)-enate (702),666 salannolactam-(23) influences the potency of 292.872 Furthermore, it was possible to (1154), and salannolactam-(21) (1155).766 In addition, azadirachtol draw some general conclusions that hydrogenation of the C-22/ (295) was reported to exhibit higher antifeedant activity than 23 enol ether double bond did not significantly diminish activity azadirachtin (292), but supporting data was lacking for this of either the azadirachtin or 11-deoxy series, and that both the claim.323 Negatively, nimbinin (60), 17-epiazadiradione (77), bulky substituents at C-22 and increasingly larger groups at C-23 and nimbin (391) were inactive against Reticulitermes speratus caused a considerable drop in antifeedancy.873,874 For example, 103 β and the PC95 values were beyond the bioassay limits. both 292 and 22,23-dihyro-23 -methoxyazadirachtin (303) As for structure activity relationship of the insect antifeedant were potent antifeedant against S. littoralis and Heliothis virescens, activity, Govindachari et al. pointed out that the C-seco limonoids whereas the latter, which had greater steric bulk at C-23, had were the most effective compounds while the intact limonoids weaker activity.305 The nature of the substituents at C-1 and C-3 were the least effective.869 Similarly, antifeedant activity tests of the decalin ring of azadirachtins affected the antifeedancy of showed that azadirachtin-class C-seco limonoids were the most the compounds, as did the additional substituents to C-22/23.875 potent ones, followed by the 12α-OH compounds of the In addition, Yamasaki et al. suggested that the hydroxyl groups on trichilin-class and azedarachins containing a 14,15-epoxide com- 292 were essential for maximum activity and that the molecule bined with either a C-19/29 acetal bridge or a C-11/19 acetal must also have a lipophilic region.876 Methylation of the hydroxyl bridge.85,209,341 Suresh et al. concluded that the most active substitutions on the azadirachtins molecule resulted in a decrease among the fifty-six limonoids were the C-ring modified limo- in antifeedant activity, as did the addition of bulky groups to the noids of the azadirachtin-class followed by the intact apo-euphol dihydrofuran ring.877 On the basis of the antifeedant potency of types having a 14,15-epoxide and either a C-19/28 lactol bridge several limonoids from Azadirachta indica, it could be suggested or a cyclohexenone A ring.870 Another supporting example is that the furan ring, the α,β-unsaturated ketone, and the hydroxyl provided by azedarachins and trichilins showing the most anti- group each played an important role in determining the feedant activity against the larvae of Spodoptera eridania at a activity.103
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Table 29. Sturctures and Sources of Pentanortriterpenoids 1063 1114, Hexanortriterpenoids 1115 1118, Hepanortriterpe- noids 1119 1126, Octanortriterpenoids 1127 1129, and Enneanortriterpenoids 1130 1131
no. compounds substitution groups and others sources
1063 2-oxo-deacetyl salannin Azadirachta indica411 1064 voamatin C R = palmityl Astrotrichilia voamatata754 1065 voamatin D R = Cin A. voamatata754 β 312,319,755 324 1066 11 -azadirachtin H R1 = Tig; R2 = OH; R3 =H; Azadirachta indica; A. excelsa
R4 = COOCH3 322,324,746 1067 marrangin (azadirachtin L) R1 = Tig; R2 =H;R3 = OAc; A. excelsa
R4 = COOCH3 α 343,747,748,756 324 1068 11 -hydroxy-12-norazadirachtin R1 = Tig; R2 =H;R3 = OH; A. indica; A. excelsa α (11-epi-azadirachtin H, 11 - azadirachtin H) R4 = COOCH3 312,317,319 1069 azadirachtin I R1 = Tig; R2 = OH; R3 =H;R4 =CH3 A. indica 749 1070 11-epi-azadirachtin I R1 = Tig; R2 =H;R3 = OH; R4 =CH3 A. indica 343 324 1071 azadirachtin M R1 = Tig; R2 =H;R3 = OH; R4 =CH2OH A. indica; A. excelsa 324 1072 azadirachtin P R1 = iVal; R2 =H;R3 = OH; R4 = COOCH3 A. excelsa 1073 moluccensin M Xylocarpus moluccensis568 750,752 1074 chuktabularin A R1 =R3 = Ac; R2 =H Chukrasia tabularis 752 1075 chuktabularin K R1 =R3 = Ac; R2 = OAc C. tabularis 752 1076 chuktabularin S R1 =R2 =H;R3 =Ac C. tabularis 752 1077 chuktabularin T R1 = Ac; R2 =R3 =H C. tabularis 750,752 1078 chuktabularin C R1 =R3 = Ac; R2 =R4 =R5 =H C. tabularis 752 1079 chuktabularin L R1 =R2 =R5 =H;R3 = Ac; R4 = OAc C. tabularis 752 1080 chuktabularin M R1 =R3 = Ac; R2 =R5 =H;R4 = OAc C. tabularis 752 1081 chuktabularin N R1 = Ac; R2 =R5 =H;R3 = propanoyl; R4 = OAc C. tabularis 752 1082 chuktabularin O R1 = Ac; R2 =R5 =H;R3 = iBu; R4 = OAc C. tabularis 752 1083 chuktabularin P R1 =R3 = Ac; R2 = OH; R4 =R5 =H C. tabularis 752 1084 chuktabularin Q R1 =R3 = Ac; R2 = OAc; R4 =R5 =H C. tabularis 752 1085 chuktabularin R R1 =R2 =R4 =R5 =H;R3 =Ac C. tabularis 751 1086 chukvelutin A R1 =R4 =H;R2 = OAc; R3 = Ac; R5 =CH3 C. tabularis 751 1087 chukvelutin B R1 =R3 = Ac; R2 = OAc; R4 =H;R5 =CH3 C. tabularis 751 1088 chukvelutin C R1 =R2 =R3 =R4 = Ac; R5 =CH3 C. tabularis 750,752 1089 chuktabularin D R1 =R2 =R3 =R4 = Ac; R5 =H C. tabularis 752 1090 chuktabularin E R1 =R5 =H;R2 =R3 =R4 =Ac C. tabularis 752 1091 chuktabularin F R1 =R2 =R3 = Ac; R4 = propanoyl; R5 =H C. tabularis 752 1092 chuktabularin G R1 =R2 =R3 = Ac; R4 = iBu; R5 =H C. tabularis 752 1093 chuktabularin H R1 =R2 =R5 =H;R3 =R4 =Ac C. tabularis 752 1094 chuktabularin I R1 =R2 = Ac; R3 =R4 =R5 =H C. tabularis 752 1095 chuktabularin J R1 =R3 =R4 =R5 =H;R2 =Ac C. tabularis 1096 chuktabularin B C. tabularis750,752 1097 chuktabrin A C. tabularis697 1098 21,24,25,26,27-pentanor-15,22-oxo-7α,23- Trichilia estipulata757 dihydroxy-apotirucalla(eupha)-1-en-3-one 1099 nimbinene R = Ac Azadirachta indica758 1100 6-deacetylnimbinene R = H A. indica758 1101 nimbandiol R = H A. indica103,104,270,758 1102 6-acetylnimbandiol R = Ac A. indica316,758 α β α 161,290,291 1103 5 ,6 ,8 -trihydroxy-28-norisotoonafolin R1 =O;R2 =H Toona ciliata α β α α 161 1104 5 ,6 ,8 ,12 -tetrahdroxy-28-norisotoonafolin R1 =O;R2 =OH T. ciliata Δ1,2 290 1105 toonaciliatin A R1 =O;R2 = OH, T. ciliata 290 1106 toonaciliatin F R1 =R2 =OH T. ciliata 290 1107 toonaciliatin G R1 = OH; R2 =H T. ciliata 291 1108 toonaciliatin H R1 = Ac; R2 =OH T. ciliata 291 1109 toonaciliatin I R1 = Ac; R2 =O T. ciliata 291 1110 toonaciliatin J R1 =R2 =OH T. ciliata 573,651,759 1111 trijugin C R1 =R2 =H Trichilia connaroides
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Table 29. Continued no. compounds substitution groups and others sources 573 1112 trijugin D R1 = Ac; R2 =H T.connaroides 573 1113 trijugin E R1 = Ac; R2 =OH T. connaroides 1114 trijugin F T. connaroides573 1115 carapolide A Carapa procera581 1116 munronin E Munronia henryi506 1117 nimolicinoic acid Azadirachta indica72 1118 ceramicine A Chisocheton ceramicus262,412 491,760 1119 entilin A R1 =R2 =H Entandrophragma utile 491,760 1120 entilin B R1 =H;R2 =Ac E. utile 761 1121 entilin C R1 =CH3;R2 =H E. utile 1122 entilin D E. utile491,762 1123 munronin F Munronia henryi506 1124 turrapubesic acid A R = Ac Turraea pubescens126 1125 turrapubesic acid B R = iBu T. pubescens126 1126 turrapubesic acid C R = Piv T.pubescens126 1127 azadironol Azadirachta indica128 1128 desfurano-6α-hydroxyazadiradione R = OH A. indica120 1129 desfurano-azadiradione R = H A. indica70,753 α α α α 70,107,753 1130 7 -acetoxy-4,4,8-trimethyl-5 -(13 Me)-17-oxa-androsta-1, R= -CH3 A. indica 14-dien-3,16-dione (13α-nimolactone) α α β 70,107,753 1131 7 -acetoxy-4,4,8-trimethyl-5 -17-oxa-androsta-1,14-dien-3, R= -CH3 A. indica 16-dione (13β-nimolactone)
When trichilin-class limonoids are tested against Spodoptera 5 10 ppm appeared to be sufficient for growth disruption of eridania, there is a remarkably clear-cut structure activity relation- Spodoptera litura at early instars age, and no juvenilizing effect ship in which the 12α-OH function was the most potent, was observed.890 Injection of 292 at higher concentration caused followed by 12β-OH, 12-desoxy, and 12α-acetoxy groups, in metabolic defects including weight reduction and metamorpho- oder of decreasing potency.194,224 Similar results indicated that sis inhibition in last larval instars of Epilachna varivestis.891 In the 12-OH functionality could be necessary for maximum activity addition, prolonged development, wing deformities, unplastici- in trichilin-class limonoids, and it appeared from the variable zation of wing lobes, development of wingless adults, and larval activities of meliatoxins A1 and A2 that even the epoxide function mortality were the characteristic features of 292 on various stages on ring D had an important role to play.878 Zhou et al. also of Dysdercus koenigii.892 concluded that isomerization of the D-ring epoxide to a 15-keto The insect growth regulating activity of azadirachtin (292) and acetylation of the 12- and 29-OH groups of trichilin-class focused its effects mainly on the molt of insects. Feeding on limonoids reduced the antifeedant activity, but the side-chain azadirachtin-sprayed creeping bentgrass caused molting disor- change at C-29 did not influence their activity.225 The highly ders and death of early instar Agrotis ipsilon and slowed feeding oxygenated 1-O-acetylkhayanolide A (1003) was the most active and stunted the growth of late instars.893 292 caused significant antifeedant among the six limonoids from Khaya senegalensis. reduction in feeding activity at 2.5 g/L, prolonged the period This finding was in agreement with the observation that the role for molting to nymphal stage, and caused 60% reduction in played by increasing oxygenation in limonoids is to increase their moltability.894 Gaaboub et al. investigated the molting inhibition biological activity.550 The introduction of the O-acetyl group of of 292 against Musca autumnalis, which involved delayed lethal 895 xylogranatin F (1156) at C-3 enhanced the antifeedant rate action, adult emergence, and pupae or adults size. The ED50 significantly (16 to 25%).638 Hydrogenation of the furan ring, values for molting inhibition by injected 292 were in the range of replacement of the acetoxyl group with methoxyl group, and 10 25 ng/larvae for fourth-instar larvae of ten insect species of saponification of the methyl ester at C-11 all increased the Triatoma, Rhodnius and Panstrongylus.896 In addition, 292 in- antifeedant activity of salannin (332) against Leptinotarsa decem- hibited cold-induced supernumerary molt of last-instar Galleria lineata. Modification of the tigloyl group also changed this mellonella and induced disturbances in larval and pupal ecdysis as activity.879 well as in the metamorphic process, thus resulting in the 5.1.2. Insects Growth Regulatory Activity. Besides the formation of various intermediates.897 Feeding inhibition is an well-known antifeedant activity, azadirachtin (292) also showed indirect effect on Rhodnius prolixus due to an interference of 292 strong insect growth regulating activity against many insects. with the endocrine system rather than through the inhibition of Since 292 did not reduce feeding in Pieris brassicae pupae, the chemoreceptors.887 Although injection 292 elicited feeding in- growth retardation and deformities were the direct effect of 292 hibition, molt inhibition against Locusta migratoria was due to and not due to lack of food.889 Nutritional analyses revealed that interference with the endocrine system rather than to the altered the insect growth inhibitory and antifeedant effects were inde- feeding behavior.898 pendent of each other and relative to the level of treatment with Azadirachtin (292) inhibited the release of ecdysone from 292.884 Furthermore, 48 h feeding of 292 on foliage treated at blowfly larval and pupal brain-ring gland complexes (BRGC)
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Figure 31. Structures of pentanortriterpenoids 1063 1114, hexanortriterpenoids 1115 1118, and hepanortriterpenoids 1119 1126, octanortri- terpenoids 1127 1129, and enneanortriterpenoids 1130 1131.
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Table 30. Structures and Sources of Simple Degraded Limonoids 1132 1149
no. compounds substitution groups and others sources
452 1132 melazolide A R1 = OH; R2 =H Melia azedarach 452 1133 3-teracrylmelazolide A R1 = OH; R2 = teracryl M. azedarach 452 1134 3-teracrylmelazolide B R1 =H;R2 = teracryl M. azedarach 1135 dysodensiol A R = β-OH Dysoxylum densiforum764 1136 dysodensiol B R = α-OH D. densiforum764 1137 dysodensiol C R = O D. densiforum764 1138 azedaralide Melia azedarach230 1139 trichiconnarin A Trichilia connaroides573 1140 trichiconnarin B T. connaroides573 206,230 1141 fraxinellonone R1 =O;R2 =H Melia azedarach 230,240,251,452 1142 fraxinellone R1 =R2 =H M. azedarach α α 206 1143 9 -acetoxyfraxinellone R1 = -OAc; R2 =H M. azedarach α α α 218 1144 9 -hydroxy-12 -acetoxyfraxinellone R1 = -OH; R2 = OAc M. azedarach α α 218,452 1145 9 -hydroxyfraxinellone R1 = -OH; R2 =H M. azedarach β β 452 1146 9 -hydroxyfraxinellone R1 = -OH; R2 =H M. azedarach α 230 1147 12 -acetoxyfraxinellone R1 =H;R2 = OAc M. azedarach α 218 1148 12 -hydroxyfraxinellone R1 =H;R2 =OH M. azedarach 1149 30-hydroxyfraxinellone M. azedarach452
Figure 32. Structures of simple degraded limonoids 1132 1149.
Table 31. Structures and Sources of N-Containing Limonoids 1150 1159
no. compounds substitution groups and others sources
1150 turraparvin D Turraea parvifolia125 1151 munronin D R = H Munronia henryi506 765 1152 munroniamide R = CO(CH2)2NHNH2 M. henryi 1153 turrapubesin B Turraea pubescens287 766 1154 salannolactam-(23) R1 =H;R2 =O Azadirachta indica 766 1155 salannolactam-(21) R1 =O;R2 =H A. indica 1156 xylogranatin F R = H; Δ14,15 Xylocarpus granatum638 1157 xylogranatin G R = Ac; Δ14,15 X. granatum638 1158 xylogranatin H R = H X. granatum638 1159 granatoine X. granatum726 without affecting its biosynthesis.899 The induction of a super- with 292, the ecdysteroid levels of Locusta migratoria could be numerary larval molt with moderate doses of the ecdysteroid drastically reduced, or delayed, or extended, or unaffected.901 ff agonist (RH-2485) and the synergistic potentiation of this e ect Josephrajkumar et al. found that when applied at ED50 doses, 292 by 292 were observed.900 Depending on the timing of injection significantly depleted the content and altered the profile of
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Figure 33. Structures of N-containing limonoids 1150 1159.
Scheme 1. Strategy for the Synthesis of Azadirachtin (292)
ecdysteroids at crucial stages. This involved modification of the 292 on larval-pupal and pupal-adult of Epilachna varivestis was ecdysteroid titer and then in turn led to changes in lysosomal interpreted as an interference with molting hormone pools.907 enzyme activity causing overt morphological abnormalities dur- It was reported that 292 induced disturbances in larval and ing the metamorphic molt.902 It seemed likely that pupation in pupal ecdysis, decreased cold-induced elevation of juvenile azadirachtin-treated Manduca sexta was inhibited by a disturbed hormone titers in the larval body, and might have an effect on ecdysteroid regulation shortly before pupal ecdysis, and 292 was the prothoracicotropic function of the brain.897 A brain factor, able to inhibit development even when individuals performed a possibly the prothoracicotropic hormone that stimulates ec- complete molt after the treatment.903 In addition, low doses of dysteroid production on the prothoracic glands, might act 292 injected into newly molted last-instar larvae of Oncopeltus directly or indirectly on both the midgut cell organization and fasciatus prolonged the intermolt stage, apparently due to a the intestinal microenvironment, interfering in the trypano- delayed ecdysteroid peak.904 In preventing normal development some survival and infection of the vector Rhodnius prolixus.908 of final-instar larvae of Heliothis virescens, 292 apparently reduced Remold established a precise correlation between administered molting hormone titers by reducing prothoracicotropic hormone dose, resulting effects, and retention of 292, and concluded that (PTTH) titers and the receptivity of prothoracic glands to azadirachtin shifted and decreased the ecdysterone, juvenile 905 909 produce ecdysone via stimulation by PTTH. Remold et al. hormone, and vitellogenin peaks concomitantly. The LC50 suggested that 292 might influence the release of trophic hormones values of 292 against ecdysone 20-monooxygenase activity from the corpus cardiacum leading to alterations in timing and ranged from 10 4 MforDrosophila melanogaster to 4 10 4 titer of morphogenetic hormone pools.906 The strong effect of for Manduca sexta.910
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Scheme 2. Synthesis of Azadirachtin and Azadirachtinin Skeleton from a Common Intermediate
Scheme 3. Chemical Conversion from Azadirachtin Skeleton to Azadirachtinin Skeleton
Scheme 4. Strategy of Synthesis of 12-Oxo-14,15-epoxy Havanensin Derivatives
Exposure to 292 reduced the fertility and fecundity of adult females.912 Most of the Locusta migratoryia treated with 292 had Myzus persicae, Nasonovia ribisnigri, Chaetosiphon fragaefolii in a no oviposition, and radioimmunoassay showed quantatively that linear, concentration-dependent manner.911 Injection of 292 only traces of ecdysteroids were present in their ovaries.913 In into newly hatched adults of Oncopeltus fasciatus affected the addition, feeding adult Epilachna varivestis with 292 for first five longevity, fecundity, and hatchability of eggs from treated days after molting decreased its reproduction, increased mortal- parents, and there were marked differences between males and ity, and delayed the onset of the oviposition.914 Moreover, 292
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Scheme 5. Synthesis of Fraxinellone (1142) Using Stereoselective Oshima-Utimoto Reaction
Table 32. Antifeedancy of Azadirachtin (292) against Insects
insects antifeedancy
322 322 Epilachna varivesti EC50 = 13 ppm; EC100 = 120 ppm μ 2 μ 2 880 E. paenulata ED50 = 0.72 g/cm ,LD50 = 1.24 g/cm (96 h) 494 Helicoverpa armigera EC50 = 0.26 ppm (for neonates), 0.4 ppm (for 3rd instar larvae) Locusta migratoria MIC = 25 ppm881 882 L. migratoria ED50 = 3 ppm 883 Ostrinia nubilalis PC50 = 3.5 ppm (for neonate larvae), 24 ppm (for 3rd-instar larvae) 884 Peridroma saucia EC50 = 0.26 ppm Pieris rapae AR = 100 (1000 ppm)507 Phyllotreta striolata MIC = 10 ppm885 886 Reticulitermes speratus PC95 = 65.293 μ 887,888 Rhodnius prolixus ED50 = 25.0 g/mL 882 Schistocerca gregaria ED50 = 0.001 ppm Spodoptera littoralis AI = 98.8 ( 1.11 (1 ppm), 100.0 ( 0.00 (10 ppm);792 99 ( 1.1(1 ppm)305 delayed the release of one or more factors from the head that the synthesis and release of neurosecretion from the A-type regulate oogenesis in Aedes aegypti.915 Ovarian development was median neurosecretory cells of S. gregaria, thereby affecting the severely reduced in azadirachtin-injected females, and the vitel- ovarian development.921 logenesis was rescuable by juvenile hormone treatment.916 Both Administration of a physiological dose of 292 into female 20-hydroxyecdysone and 292 caused inhibition of vitellogenesis Locusta migratoria by injection led neither to starvation (though and ultrastructural damages in corpus allatum cells. Interestingly, food consumption was reduced) nor to a qualitative change in some ultrastructural modifications were specific to each mole- the neurosecretory proteins of the corpus cardiacum.922 How- cule, suggesting that they would act via different mechanisms.917 ever, the neurosecretory system was accompanied by an un- The vitellogenesis inhibition produced by 292 in Labidura usually high accumulation of paraldehyde fuchsin (PAF)-stainable riparia consisted of direct cytotoxic effects as well as a genera- neurosecretory material in the brain fibers and in the storage lized disruption of endocrine and neuroendocrine functions.918 lobes of the corpus cardiacum.923 The morphological and Spermiogenesis of Mamestra brassicae occurred in Grace’s med- biochemical effects induced by 292 suggested a widespread ium when the testis sheath was also present, but even in the blockade of factors presumably located in the central nervous presence of both ruptured testis and 20-hydroxyecdysone, system.924 292 stimulated a specific deterrent neuron in the 3 ppm of 292 caused degenerated spermatocysts.919 Nisbet lepidopterous species tested and inhibited the firing of neurons et al. reported that 292 bound preferentially to sites on the with signal phagostimulants in another test.925 organelles associated with maturing Schistocerca gregaria sperm Experiments in vivo and in vitro proposed by Mordue et al. tails, and that 292 at concentrations of 10 4 M and above caused demonstrated that treatment with 292 resulted in a significant a time-dependent reduction in the motility of eupyrene sperm growth reduction in the rate of passage of food through the gut, bundles liberated from the accessory glands of mature male and in gut motility of Locusta migratoria.926 Furthermore, S. gregaria.920 Subrahmanyam et al. pointed out that 292 delayed azadirachtin (292) directly or indirectly inhibited the reduction
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Table 33. Antifeedancy of Meliaceous Limonoids
compounds insects and antifeedancy
azadirone (1) Leptinotarsa decemlineata, AI = 11.6 ( 6.3 (100 ppm), 22.4 ( 7.4 (300 ppm), 26.9 ( 5.1 (500 ppm)273 μ 103 101 azadiradione (12) Reticulitermes speratus,PC95 = 827.5 g/disk; Heliothis virescens,EC50= 560 ppm 101 7-deacetylazadiradione (13) H. virescens,EC50 = 1600 ppm β μ 103 17 -hydroxyazadiradione (18) Reticulitermes speratus,PC95 = 235.6 g/disk β 101 7-deacetyl-17 -hydroxyazadiradione (19) Heliothis virescens,EC50 = 240 ppm μ 191 nilotin (129) Leptinotarsa decemlineata,ED50 =7 g/mL α μ 2 μ 2 12 -hydroxyamoorastatin (166) Epilachna paenulata,ED50 = 0.80 g/cm (in choice assay); LD50 = 0.76 g/cm (in no-choice assay)880 865 chuanliansu (167) Helicoverpa armigera,EC50 = 26.8 ppm; FI50 = 56.6 ppm (for third-instar larvae) μ 2880 Epilachna paenulata,ED50 = 3.69 g/cm 1β,2β;21,23-diepoxy-7α-hydroxy-24,25,26,27-tetranor- Leptinotarsa decemlineata, AI = 10.8 ( 4.5 (100 ppm), 21.4 ( 2.6 (300 ppm), apotirucalla-14,20,22-trien-3-one (246) 24.9 ( 3.7 (500 ppm)273 322 322 3-tigloylazadirachtol (296) Epilachna varivesti,EC50 = 30 ppm; EC100 = 150 ppm μ 872 Schistocerca gregaria,ED50 =80 g/l 872 Locusta migratoria,ED50 = 12 mg/L 322 322 1-tigloyl-3-acetylazadirachtol (297) Epilachna varivesti,EC50 = 6 ppm; EC100 = 50 ppm μ 2 362 μ 103 salannin (332) Spodoptera frugiperda,ED50 =13 g/cm ; Reticulitermes speratus,PC95 = 203.3 g/disk μ 103 3-deacetylsalannin (333) R. speratus,PC95 = 1373.1 g/disk 322 322 nimbolide (345) Epilachna varivesti,EC50 = 90 ppm; EC100 > 500 ppm μ 2362 volkensin (369) Spodoptera frugiperda,ED50 = 3.5 g/cm μ 103 6-deacetylnimbin (392) Reticulitermes speratus,PC95 = 1581.2 g/disk μ 103 gedunin (416) R. speratus,PC95 = 218.4 g/disk μ 103 7-deacetylgedunin (421) R. speratus,PC95 = 113.7 g/disk 494 prieurianin (458) Helicoverpa armigera,EC50 = 18.8 ppm (for neonates), EC50 = 92.2 ppm (for 3rd instar larvae) 494 epoxyprieurianin (464) H. armigera,EC50 = 3.2 ppm (for neonates), EC50 = 55.7 ppm (for 3rd instar larvae) dysoxylumin A (465) Pieris rapae, AR = 73.8 (1000 ppm)507 dysoxylumin B (466) P. rapae, AR = 77.4 (1000 ppm)507 dysoxylumin C (467) P. rapae, AR = 74.9 (1000 ppm)507 dysoxylumolide B (501) P. rapae, AR = 28.3 (1000 ppm)507 dysoxylumic acid D (502) P. rapae, AR = 29.5 (1000 ppm)507 dysoxylumic acid A (503) P. rapae, AR = 78.7 (1000 ppm)507 dysoxylumic acid B (504) P. rapae, AR = 64.1(1000 ppm)507 dysoxylumic acid C (506) P. rapae, AR = 59.4 (1000 ppm)507 dysoxylumolide A (512) P. rapae, AR = 27.9 (1000 ppm)507 dysoxylumolide C (554) P. rapae, AR = 22.4 (1000 ppm)507 methyl angolensate (568) Spodoptera frugiperda, AI = 66.4 ( 10.63 (1000 ppm)556 swietenolide (638) S. frugiperda, AI = 94.1 ( 2.90 (1000 ppm)445 6-acetylswietenolide (645) S. frugiperda, AI = 72.2 ( 19.60 (1000 ppm)445 diacetylswietenolide (647) S. frugiperda, AI = 72.0 ( 9.38(1000 ppm)445 xylocarpin (799) S. frugiperda, AI = 77.8 ( 6.90 (1000 ppm)556 swietemahonin F (805) S. frugiperda, AI = 70.2 ( 8.90 (1000 ppm)445 ruageanin A (808) S. frugiperda, AI = 72.6 ( 19.60 (1000 ppm)556 ruageanin B (809) S. frugiperda, AI = 86.3 ( 6.41(1000 ppm)556 678 khayanolide A (1002) S. littoralis, EC50 = 11.18 mg/kg 678 khayanolide B (1004) S. littoralis, EC50 = 2.19 mg/kg 678 1-O-acetylkhayanolide B (1005) S. littoralis, EC50 = 2.66 mg/kg 322 322 marrangin (1067) Epilachna varivesti,EC50 = 6 ppm; EC100 = 50 ppm μ 103 nimbandiol (1101) Reticulitermes speratus,PC95 = 245.4 g/disk munroniamide (1152) Pieris brassicae, AR = 27.6 (1000 ppm)765 of trypsin by the enzyme-secreting cells of the midgut wall and growth.927 When Spodoptera litura larvae were fed a diet of castor consequently resulted in the increased costs and reduced rate of leaves treated with 292, gut enzyme-acid phosphatases, alkaline
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Table 34. MAC Values (ppm) of Antifeedancy of Meliaceous Limonoids
compounds insects MAC values
trichilin B (137) Spodoptera exigua;207,220,341 S. littoralis214 200 12-O-acetyltrichilin B (138) S. exigua220,341 400 1,12-diacetyltrichilin B (139) S. exigua207,220,341 trichilin D (141) S. exigua207,220 aphanastatin (142) S. exigua and S. eridania341 200 trichilin F (143) S. littoralis223 300 trichilin G (144) S. littoralis223 trichilin H (145) S. exigua;207,220,227,341 S. eridania224 400 1-acetyltrichilin H (146) S. littoralis225 trichilin I (151) S. exigua;220,227,341 S. eridania224 trichilin J (153) S. exigua;220,227,341 S. eridania224 trichilin K (154) S. eridani224 trichilin L (155) S. eridani224 sendanin (156) S. littoralis214 azedarachin A (158) S. exigua;207,227,341 S. eridania224,341 200 12-O-acetylazedarachin A (159) S. exigua;207,341 S. eridania341 S. littoralis214 400 azedarachin B (160) S. littoralis214,225 200 12-O-acetylazedarachin B (161) S. eridani;224 S. exigua207,227 400 azedarachin C (162) S. exigua228,341 878 meliatoxin A2 (163) S. litura 300 S. exigua;207,341 S. eridania341 400 12α-hydroxyamoorastatin (166) S. littoralis214 150 toosendanin (167) S. littoralis212 200 S. littoralis214 300 12α-hydroxyamoorastatone (173) S. littoralis225 250 isochuanliansu (179) S. littoralis214 400 S. littoralis225 300 neoazedarachins A, B, D (180 182) S. littoralis225 400 1-cinnamoyltrichilinin (192) S. littoralis212 1000 trichilinin B (195) S. eridania239 trichilinin C (196) S. eridania239 trichilinin D (197) S. littoralis212,247 trichilinin E (198) S. littoralis212,247 meliacarpinin A (327) S. exigua;341 S. littoralis214 50 meliacarpinin B (328) S. exigua340 150 S. exigua and S. eridania341 50 meliacarpinin C (329) S. exigua and S. eridania,341 S. littoralis214 50 meliacarpinin D (330) S. exigua and S. eridania,341 S. littoralis214 meliacarpinin E (331) S. eridania342 salannin (332) S. exigua;341 S. eridania84,239,341,342,363 1000 3-deacetylsalannin (333) S. eridania342 nimbolinin A (355) S. littoralis212 1-deacetylnimbolinin A (356) S. littoralis247 nimbolinin B (358) S. exigua;341 S. eridania341,342 S. littoralis247 nimbolinin C (363) S. littoralis212 nimbolinin D (364) S. littoralis212 ohchinolide C (386) S. eridania84 3-O-acetylohchinolal (399) S. eridania84 nimbolidin B (407) S. eridania247,342 1000 S. eridania363 500 nimbolidins C-E (410 412) S. eridania363 500 nimbolidin F (413) S. eridania84
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Table 34. Continued compounds insects MAC values Trs A-C (462, 479, 463) Ajrotis sejetum Denis493 200 methyl angolensate (568) Spodoptera littoralis547 549,551 500 methyl 6-hydroxyangolensate (569) S. littorali547 549 methyl 6-acetoyxangolensate (570) S. littoralis547,549 sandoricin (573) and 6-hydroxysandoricin (574) S. frugiperda532 25 Ostrinia nubilalis532 200 khayanoside (598) Spodoptera littoralis574 1000 proceranolide butanoate (635) Agrotis segetum648 100 khayanone (668) Spodoptera littoralis658 300 angolensins A-C (672, 766, and 673) S. littoralis545 1000 8β,14α-dihydroxyswietenolide (674) S. littoralis510 500 khayalactol (774) S. littoralis547 300 seneganolide (777) S. littoralis547,549,551 2-hydroxyseneganolide (778) S. littoralis559,658 200 2-hydroxyswietemahonolide (797) S. littoralis630 500 swietemahonin G (806) S. littoralis630 300 6-O-acetylswietemahonin G (807) S. littoralis630 500 xyloccensin L (829) Piece brassicae635 1000 tabulalide D (857) Spodoptera littoralis706 500 swietenialides A E(921 923, 889, 895) S. littoralis664 1000 xyloccensins P, Q (949, 950) Mythimna separata700 500 tabulalin (973) Spodoptera littoralis706 tabulalides A, B, E (995, 996, and 978) S. littoralis706 1000 khayanolide A (1002) S. littoralis547 549 300 1-O-acetylkhayanolide A (1003) S. littoralis559,658 100 khayanolide B (1004) S. littoralis547 549 1000 1-O-acetylkhayanolide B (1005) S. littoralis547 300 khayanolide D (1006) S. littoralis559 200 S. littoralis574 1000 khayanolide E (1007) S. littoralis574 100 khayanolide C (1013) S. littoralis549 500 spirosendan (1056) S. littoralis247 1000 azedararide (1138) S. littoralis230 500 fraxinellone (1142) S. littoralis230 12α-acetoxyfraxinellone (1147) S. littorali230 phosphatases, adenosine triphosphatases, and lactate dehydro- inhibitor but comparably effective in ecdysis inhibition.316,843 genase decreased.928 Surprisingly, salannin (332) was comparable to 292 in growth- Using Drosophila melanogaster as model system, the insect regulatory activity against Spodoptera litura, Pericallia ricini, and cellular cytoskeletal β-actin was found to be the probable target Oxya fuscovittata.934 929,930 of azadirachtin (292). Azadirachtin (292), salannin (332), Nimocinolide (26) and isonimocinolide (29)affected fecund- nimbin (391), and 6-deacetylnimbin (392) inhibited the ecdy- ity in Musca domestica at doses of 100 500 ppm and showed sone 20-monooxygenase (E-20-M) activity against Aedes aegypti, mutagenic properties in Aedes aegypti producing intermediates.80 Drosophila melanogaster, and Manduca sexta in a dose-dependent Nutritional analyses revealed that both growth inhibition and fashion. Based on the dose reponse as well as the 50% inhibition reduced consumption of cedrelone (81) were a consequence of ff (I50) value, 332 was found to be the most e ective whereas 391 postingestive malaise rather than a peripherally mediated anti- ff 931 ff β ff 935 was the least e ective. The e ects of 17 -hydroxyazadiradione feedant e ect. The feeding experiments showed the ED50 (18), 292, 332, 3-deacetylnimbin (333), gedunin (416), and values of sendanin (156) for growth inhibition against Pectino- 7-deacetylgedunin(421) on enzyme lactate dehydrogenase phora gossypiella, Heliothis zea, H. virescens, and Spodoptera (LDH) activity of Cnaphalocrocis medinalis larvae were investi- frugiperda ranged from 9 to 60 ppm, with P. gossypiella being gated with clear dose response dependency manner. Among the most sensitive and Heliothis complex the least.198 When these compounds, 292 is most potent in all experiments with incorporated into artificial diets of neonates at 50 ppm, humilinolides EC50 values at least 0.043, 0.057, and 0.063 ppm for third, fourth A D(793, 794, 695, and 697) caused larval mortality, as well as and fifth instars, respectively.932,933 Azadirachtin B (296) was growth reduction and increased the development time of survi- 2.5-fold less active than azadiracthin (292) as an insect growth vors in a concentration-dependent manner. In addition, 695 at
BK dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 35. Insects Growth Regulatory Activity of Meliaceous Limonoids
compounds insects and efficacy
170 hirtin (94) Peridroma saucia,EC50 = 13 ppm 413 toosendanin (167) Spodoptera frugiperda,LC50 = 7.0 ppm 936 azadirachtin (292) Heliothis zea and H. virescens,ED50 = 0.7 ppm; Spodoptera frugiperda, Pectinophora gossypiella,ED50 = 0.4 ppm μ 888 Rhodnius prolixus,ED50 = 0.04 g/mL 442 Helicoverpa armigera,EC50 = 0.26 ppm; Spodoptera litura,EC50 = 0.21 ppm μ 888 azadirachtin B (296) Rhodnius prolixus,ED50 = 0.015 g/mL 442 366 salannin (332) Helicoverpa armigera,EC50 = 74.5 ppm, EC50 = 86.5 ppm, EC95 = 187.4 ppm 442 Spodoptera litura,EC50 = 72.0 ppm μ 2366 S. litura, EC50 = 87.7 ppm, EC95 = 197.3 ppm and FI50 = 2.8 g/cm μ 2366 salannol (336) S. litura,EC50 = 77.4 ppm, EC95 = 220.8 ppm, and FI50 = 2.3 g/cm 366 Helicoverpa armigera,EC50 = 79.7 ppm, EC95 = 219.7 ppm 366 salannol acetate (337) H. armigera,EC50 = 64.2 ppm, EC95 = 166.9 ppm μ 2366 Spodoptera litura,EC50 = 65.6 ppm, EC95 = 169.1 ppm, and FI50 = 2.0 g/cm 442 gedunin (416) Spodoptera litura,EC50 = 40.4 ppm 413 S. frugiperda,LC50 = 39.0 ppm 442 Helicoverpa armigera,EC50 = 50.8 ppm β 442 6 -hydroxygedunin (420) H. armigera,EC50 = 24.2 ppm; Spodoptera litura,EC50 = 21.5 ppm 413 photogedunin (433) S. frugiperda,LC50 = 10.0 ppm 5 498 prieurianin (458) Drosophila melanogaster,ED50 =10 M 4 498 rohitukin (480) D. melanogaster,ED50 = 1.25 10 M 678 khayalactol (774) Spodoptera littoralis, EC50 = 11.48 mg/kg 678 khayanolide A (1002) S. littoralis, EC50 = 14.65 mg/kg 678 khayanolide B (1004) S. littoralis, EC50 = 6.96 mg/kg 678 1-O-acetylkhayanolide B (1005) S. littoralis, EC50 = 16.75 mg/kg 442 nimbinene (1099) S. litura,EC50 = 404.5 ppm; Helicoverpa armigera,EC50 = 394.1 ppm
5 ppm also reduced growth and survivorship of Ostrinia Swietenin C (679), humilinolide E (698), methyl-2-hydroxy- nubilalis.665 3β-isobutyroxy-1-oxomeliac-8(30)-enate (699), and humilin B β The EC50 values of 7-deacetyl-17 -hydroxyazadiradione (19), (812) reduced survivorships at various stages against Ostrinia azadiradione (12), and nimbocinol (13) against Heliothis sires- nubilalis, while 6α-acetoxygedunin (418) reduced growth at the cens were 240, 560, and 1600 ppm, respectively, which suggested test concentration of 50 ppm.434 Khayasin (652) exhibited that the insect growth regulating activity was reduced by a marked insecticidal activity against the fifth larvae of Brontispa hydroxyl group at C-7 but increased by a hydroxyl group at longissima at a concentration of 10 mg/L.558 Among khayasin T C-17.101 Siddiqui et al. proposed that the senecioyloxy substi- (655), febrifugin (694), cipadesin (703), ruageanin A (808), tuent at C-7 in 7-O-deacetyl-23-O-methyl-7α-O-senecioylnimo- cipadesin A (815), and febrifugin A (716), the last showed the cinolide (28) resulted in a significant increase of insect growth hightest insecticidal activity at 50.0 mg/kg against Spodoptera regulating activity against Aedes aegypti.119 frugiperda, comparable to that of the positive control-gedunin 5.1.3. Insecticidal Activity. The insecticidal activities of (416).656 Moluccensins H and I (964 and 965) showed mod- azadirachtin-like compounds were listed in detail by Govinda- erate insecticidal activity against the fifth instar larvae of Brontispa chari et al. in 1998.937 We now summarize the insecticidal efficacy longissima at a concentration of 100 mg/L, whereas moluccensins 568 of limonoids in Table 36. The LC50 values of 292 against the second- J L(966, 969, 970) exhibited no activity. Preliminary studies instar nymphs of nine species of aphids ranged from 2.4 ppm for showed that the limonoids and triterpenoids in Cedrela fissilis and Myzus persicae on pepper to 635.0 ppm for Chaetosiphon fragaefolii C. fruticosa were promising in controlling leaf-cutting ants Atta 938 671 on strawberry. Contact and dipping LC50 values of 292 against sexdens rubropilosa, and subsequent research revealed that the larvae of Hyalomma dromedarii were >20.3 μg/cm2 and >2.5 g/L, toxicity for the ants seemed not to be related only to the presence respectively.894 Arnason et al. proved that 292 was an effective of the limonoids.113 Neither 53 nor 20,21,22,23-tetrahydro-23- botanical insecticide for control of Ostrinia nubilalis at 10 ppm.883 In oxoazadirone (56) showed insecticidal activity against Peridroma addition, 292 was efficacious against Haematobia irritans, Stomoxys saucia.131 In addition, meliacinol (456) did not show insecticidal calcitrans,andMusca domestica andalsohadpotentialforH. irritans activity against Aedes aegypti at up to 100 ppm.93 control.939 It was announced that 292 in ppm concentrations inhi- Quantitative molecular calculations of the structure activity bited proliferation and monolayer formation of Spodoptera frugiperda relationship indicated that the insecticidal activity of azadirach- (Sf9) insect cells in monolayer culture.831,940 However, Cohen et al. tins was directly proportional to the polarity of ring A, the steric stated that 292 was not cytotoxic against Sf9 cell lines.941 The requirements of the substituents at C-7, and the rotations around evidence presented by Salehzadeh et al. suggested that in insect cells the single bond between C-8 and C-14.943 The potent larvicidal 292 acted similarly to the antimitotic plant metabolite colchicine, activity of gedunin (416) indicated that the epoxidation and namely, by interfering with the polymerization of tubulin.942 expansion of ring D had a favorable effect on this activity, as was
BL dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 36. Insecticidal Efficacy of Meliaceous Limonoids
compounds insects and efficacy
93 nimocinol (7) Aedes aegypti,LC50 = 21 ppm α 93 6 -O-acetyl-7-deacetylnimocinol (8) A. aegypti,LC50 = 83 ppm 119 23-O-methylnimocinolide (27) A. aegypti,LC50 = 53 ppm α 119 7-O-deacetyl-23-O-methyl-7 -O-senecioylnimocinolide (28) A. aegypti,LC50 = 2.14 ppm 120 22,23-dihydronimocinol (33) Anopheles stephensi,LC50 = 60 ppm α α β α α 188 1 ,7 ,11 -triacetoxy-4 -carbomethoxy-12 - A. gambiae,LD50 = 4.0 ppm (2-methylpropanoyloxy)-14β,15β-epoxyhavanensin (123) α β α α α 188 1 ,11 -diacetoxy-4 -carbomethoxy-7 -hydroxy-12 - A. gambiae,LD50 = 3.6 ppm (2-methylpropanoyloxy)-15-oxohavanensin (130) α α 188 1 -acetyl-3 -propionylvilasinin (187) A. gambiae,LD50 = 7.1 ppm 272 meliatetraolenone (245) A. stephensi,LC50 = 16 ppm 188 azadirachtin (292) A. gambiae,LD50 = 57.1 ppm Plutella xylostella,LD50 = 7.04 (24 h); 4.12 (48 h); 1.28 (72 h); μ 324 338 0.87 (96 h) g/g Spodoptera littoralis,LC50 = 0.32 ppm, EC50 = 0.11 ppm μ 324 azadirachtol (295) Plutella xylostella,LD50 = 4.88 (24 h); 3.28 (48 h); 2.35 (72 h); 1.78 (96 h) g/g μ 324 azadirachtin B (296) P. xylostella,LD50 = 4.85 (24 h); 2.26 (48 h); 1.56 (72 h); 1.06 (96 h) g/g μ 324 azadirachtin O (301) P. xylostella,LD50 = 3.92 (24 h); 1.92 (48 h); 1.19 (72 h); 0.79 (96 h) g/g μ 324 azadirachtin Q (302) P. xylostella,LD50 = 5.95 (24 h); 1.89 (48 h); 1.40 (72 h); 1.10 (96 h) g/g 338 1,3-dicinnamoyl-11-hydroxymeliacarpin (313) Spodoptera littoralis,LC50 = 2.36 ppm, EC50 = 0.57 ppm 338 1-cinnamoyl-3-acetyl-11-hydroxymeliacarpin (314) S. littoralis,LC50 = 0.48 ppm 338 1-cinnamoyl-3-methacrylyl-11-hydroxymeliacarpin (315) S. littoralis,LC50 = 1.19 ppm, EC50 = 0.57 ppm α α β 579 7 ,12 -diacetyoxy-11 -hydroxyneotecleanin (621) Anopheles gambiae,LD50 = 7.83 ppm β α 579 11 ,12 -diacetoxyneotecleanin (622) A. gambiae,LD50 = 7.07 ppm β α β β 579 11 ,12 -diacetoxy-14 ,15 -epoxyneotecleanin (623) A. gambiae,LD50 = 7.05 ppm μ 324 azadirachtin L (1067) Plutella xylostella,LD50 = 10.27 (24 h); 7.89 (48 h); 5.39 (72 h); 1.92 (96 h) g/g α μ 324 11 -azadirachtin H (1068) P. xylostella,LD50 = 5.75 (24 h); 4.20 (48 h); 1.38 (72 h); 0.75 (96 h) g/g μ 324 azadirachtin M (1071) P. xylostella,LD50 = 8.46 (24 h); 4.84 (48 h); 4.23 (72 h); 1.30 (96 h) g/g μ 324 azadirachtin P (1072) P. xylostella,LD50 = 2.19 (24 h); 1.73 (48 h); 1.19 (72 h); 0.79 (96 h) g/g α 120 desfurano-6 -hydroxyazadiradione (1128) Anopheles stephensi,LC50 = 43 ppm also the case for the CdC bond in the ring A in nimbocinol (13) (Bacillus subtilis, Aspergillus fumigatus, A. niger, and Alternaria and nimolicinol (451).944 alternata), methyl angolensate (568) exhibited the maximum 5.1.4. Antiphytopathogen Activity. Interestingly, pure zone of inhibition (17.3 mm) against A. niger.947 mexicanolide azadiradione (12), epoxyazadiradione (60), salannin (332), (626), 2α,3β-dihydroxy-3-deoxymexicanolide (628), 3β-hydro- and nimbin (391) did not have appreciable antifungal activity. xy-3-deoxymexicanolide (629), 6-acetyl-3-tigloylswitenolide However, when these limonoids were mixed and bioassayed, (646), and 6-acetylswietenine (687) effectively reduced the they showed antifungal activity against Drechslera oryzae, Alter- number of rust pustules on detached groundnut leaves.603 naria tenuis, and Fusarium oxysporum f. sp. vasinfectum, indicating 2-Acetoxyseneganolide (725) at concentrations of 1000 and possible additive/synergistic effects.105 Among azadiradione 1500 ppm showed inhibitions against B. cinerea growth of (12), cedrelone (81), and several derivatives of 81, the most 61.50% and 68.33%, respectively, which differ only insignificantly effective in reducing rust pustule emergence was 81 itself, which from the inhibitions yielded by methyl 6-hydroxyangolensate gave emergence reductions of 98.4% and 93.4% at concentra- (569) at 1500 ppm (65.33%) and seneganolide A (723) at 1000 tions of 1 μg/cm2 and 10 μg/cm2, repectively.945 The results ppm (60.83%).472 1,2-Dihydro-6α-acetoxyazadirone (239) sho- obtained by Kraus et al. showed that nimbolide (345) inhibited wed strong inhibitory properties against the pathogenic fungi Bacillus subtilis even at a concentration of 0.5 μg/spot.322 Nimbin Curvularia verruciformis, Dreschlera oryzae, and Alternaria solani, (391) inhibited the growth of potato virus X in vitro by <50% at a but no related data were presented in the original paper.267 concentration of 1000 ppm.946 Ten limonoids from Khaya 6-Acetoxy-7α-hydroxy-3-oxo-14β,15β-epoxymeliac-1,5-diene ivorensis were tested antifungal activity against Botrytis cinerea, (69) exhibited strong antibacterial activity against Bacillus anti- and among these 1,3,7-trideacetylkhivorin (438) and 568 macis, B. pumilus, and B. subtilis, but no data were provided in the showed the highest activity, while 7-deacetylgedunin (421) had original paper.142 the lowest activity.447 With the exception of Penicillium expan- 5.1.5. Others. Cherry found that 292 did not cause mortality, sum,3α,7α-dideacetylkhivorin (440) showed stronger antimi- antifeeding responses, or change the growth rate of Melanotus crobial activity than methyl 6-hydroxyangolensate (569) against communis wireworms; however, azadirachtin-treated soil was all of the fungi tested (Aspergillus niger, Monilinia fructicola, repellent to the wireworms.948 7-Deacetoxy-7-oxogedunin (423) Botrytis cinerea, Geotrichum candidum, Colletotrichum acutatum, acted as an inhibitor of photophosphorylation in spinach thyla- Penicillium expansum, P. italicum, Glomerella cingulata, and Phy- koids since it inhibited ATP synthesis and phosphorylating tophthora citrophthora).447 Among the microbial species tested electron flows by 88 and 83%, respectively, at a concentration
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Table 37. Cytotoxic Activity of Meliaceous Limonoids against Tumor Cell Lines
compounds cells activity μ 97 dysobinin (11)KBIC50 = 3.17 g/mL μ 97 NCI-H187 IC50 = 1.67 g/mL μ 97 MCF7 IC50 = 2.15 g/mL μ 97 azadiradione (12)KBIC50 = 9.38 g/mL μ 97 NCI-H187 IC50 = 6.44 g/mL μ 97 MCF7 IC50 = 7.13 g/mL μ 97 mahonin (17) NCI-H187 IC50 = 15.61 g/mL μ 97 MCF7 IC50 = 18.42 g/mL μ 500 epoxyazadiradione (nimbinin) (60) GPK ED50 = 7.13 g/mL μ 97 KB IC50 = 12.87 g/mL μ 97 NCI-H187 IC50 = 7.54 g/mL μ 97 MCF7 IC50 = 4.68 g/mL 115 μ 941 N1 10 IC50 =23 M μ 941 143B.TK IC50 =24 M μ 210 anthothecol (84) P388 ED50 = 1.2 g/mL μ 221 1,12-diacetyltrichilin B (139) P388 IC50 = 0.46 g/mL μ 221 trichilin D (141) P388 IC50 = 0.055 g/mL μ 221 trichilin H (145) P388 IC50 = 0.16 g/mL μ 211 KB IC50 = 0.11 g/mL μ 221 1-acetyltrichilin H (146) P388 IC50 = 0.47 g/mL μ 221 1-acetyl-2-deacetyltrichilin H (147) P388 IC50 = 0.66 g/mL μ 221 3-deacetyltrichilin H (148) P388 IC50 = 0.045 g/mL μ 221 1-acetyl-3-deacetyltrichilin H (149) P388 IC50 = 0.40 g/mL μ 226 12-O-deacetyltrichilin H (150) HeLa S3 IC50 = 0.48 M μ 221 12-deacetyltrichilin I (152) P388 IC50 = 0.011 g/mL μ 205 μ 210 sendanin (156) P388 IC50 = 0.078 g/mL; ED50 = 0.01 g/mL 115 μ 941 N1 10 IC50 = 133 M μ 941 143B.TK IC50 =89 M μ 202 29-deacetylsendanin (157) Hepa1c1c7 GI50 = 0.238 g/mL μ 202 HepG2 GI50 = 0.805 g/mL μ 205 P388 IC50 = 0.026 g/mL μ 205 29-isobutylsendanin (161) P388 IC50 = 0.034 g/mL α μ 210 μ 205 12 -hydroxyamoorastatin (166) P388 ED50 = 0.002 g/mL; IC50 = 0.090 g/mL μ 211 toosendanin (167)KBIC50 = 3.82 g/mL 7 960 PC3 IC50 = 1.2 10 M (120 h) 8 960 BEL7404 IC50 = 2.6 10 M (96 h) 7 960 SH-SY5Y IC50 = 1.5 10 M (96 h) 8 960 U251 IC50 = 3.3 10 M (96 h) 9 960 HL-60 IC50 = 6.1 10 M (96 h) 9 960 U937 IC50 = 5.4 10 M (72 h) μ 210 amoorastatone (172) P388 ED50 =30 g/mL μ 221 meliatoxin B1 (177) P388 IC50 = 5.4 g/mL μ 211 KB IC50 >10 g/mL μ 211 toosendanal (185)KBIC50 >10 g/mL μ 248 meliavolkin (200) A-549 ED50 = 0.57 g/mL μ 248 MCF-7 ED50 = 0.26 g/mL μ 248 HT-29 ED50 = 0.12 g/mL μ 242 malleastrone A (227) A2780 IC50 = 0.49 M μ 242 MDA-MB-435 IC50 = 0.41 M μ 242 HT-29 IC50 = 0.24 M μ 242 H552-T1 IC50 = 0.24 M μ 242 U937 IC50 = 0.20 M μ 242 malleastrone B (228) A2780 IC50 = 0.63 M μ 242 MDA-MB-435 IC50 = 0.34 M
BN dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 37. Continued compounds cells activity μ 242 HT-29 IC50 = 0.22 M μ 242 H552-T1 IC50 = 0.23 M μ 242 U937 IC50 = 0.19 M μ 242 malleastrone C (229) A2780 IC50 =18 M μ 287 turrapubesin A (290) P388 IC50 = 12.14 M μ 205 1-tigloyl-3-acetyl-11-methoxymeliacarpinin (318) P388 IC50 = 3.2 g/mL μ 345 1-tigloyl-3,20-diacetyl-11-methoxymeliacarpinin (321) P388 IC50 = 100 g/mL μ 345 3-tigloyl-1,20-diacetyl-11-methoxymeliacarpinin (322) P388 IC50 =48 g/mL μ 345 1-cinnamoyl-3-hydroxy-11-methoxymeliacarpinin (323) P388 IC50 = 1.5 g/mL μ 345 1-deoxy-3-methacrylyl-11-methoxymeliacarpinin (324) P388 IC50 =47 g/mL μ 345 1-cinnamoyl-3-acetyl-11-methoyxmeliacarpinin (327) P388 IC50 = 10.5 g/mL μ 205 1-acetyl-3-tigloyl-11-methoxymeliacarpinin (329) P388 IC50 = 3.3 g/mL μ 500 nimbolide (345) GPK ED50 = 10.14 g/mL 115 μ 961 μ 941 N1 10 IC50 = 1.5 g/mL; 5.2 M μ 941 143B.TK IC50 = 4.3 M μ 373 μ 369 BC-1 ED50 = 0.39 g/mL; 3.1 g/mL μ 373 μ 369 COL-2 ED50 = 0.41 g/mL; 4.2 g/mL μ 373 HT-1080 ED50 = 0.31 g/mL μ 373 μ 369 LU-1 ED50 = 0.42 g/mL; 3.3 g/mL μ 373 MEL-2 ED50 = 0.53 g/mL μ 373 μ 369 KB ED50 = 0.25 g/mL; 1.7 g/mL μ 373 P388 ED50 = 0.065 g/mL μ 369 LNCaP ED50 = 0.9 g/mL μ 373 μ 369 28-deoxonimbolide (346) BC-1 ED50 = 1.34 g/mL; 3.2 g/mL μ 373 μ 369 COL-2 ED50 = 1.81 g/mL; 9.0 g/mL μ 373 HT-1080 ED50 = 1.04 g/mL μ 373 μ 369 LU-1 ED50 = 0.84 g/mL; 8.5 g/mL μ 373 MEL-2 ED50 = 2.05 g/mL μ 373 μ 369 KB ED50 = 1.30 g/mL; 4.1 g/mL μ 373 P388 ED50 = 0.66 g/mL μ 369 LNCaP ED50 = 1.9 g/mL μ 211 12-O-methylvolkensin (370)KBIC50 = 8.72 g/mL μ 387 1-O-deacetylohchinolide A (372) HeLa S3 IC50 = 2.40 M μ 387 1-O-deacetyl-1-O-tigloylohchinolide A (373) HeLa S3 IC50 = 29.7 M μ 387 ohchinolide B (374) HeLa S3 IC50 = 40.5 M μ 387 1-O-deacetylohchinolide B (375) HeLa S3 IC50 = 0.10 M μ 387 1-O-deacetyl-1-O-tigloylohchinolide B (376) HeLa S3 IC50 = 33.8 M μ 387 1-O-deacetyl-1-O-benzoylohchinolide B (377) HeLa S3 IC50 = 33.0 M μ 390 chisonimbolinin C (380) HeLa IC50 =13 M μ 390 chisonimbolinin D (381) HeLa IC50 =32 M μ 226 15-O-deacetyl-15-O-methylnimbolindin A (406) HeLa S3 IC50 = 37.4 M μ 226 15-O-deacetylnimbolindin B (408) HeLa S3 IC50 = 0.10 M μ 226 15-O-deacetyl-15-O-methylnimbolindin B (409) HeLa S3 IC50 = 28.3 M μ 412 walsogyne A (414) P388 IC50 =5 g/mL μ 49 gedunin (416) CaCo-2 IC50 = 16.83 M μ 500 GPK ED50 = 275.10 g/mL μ 433 P388 IC50 = 3.3 g/mL μ 448 7-deacetylgedunin (421) CHAGO IC50 = 16.00 M μ 448 Hep-G2 IC50 = 10.26 M μ 433 P388 IC50 = 4.5 g/mL μ 448 7-deacetoxy-7-oxogedunin (423) Hep-G2 IC50 = 16.17 M α β μ 433 7-deacetoxy-7 ,11 -dihydroxygedunin (424) P388 IC50 = 7.8 g/mL α μ 433 11 -hydroxygedunin (426) P388 IC50 =71 g/mL β μ 433 11 -hydroxygedunin (427) P388 IC50 = 5.4 g/mL μ 433 11-oxogedunin (429) P388 IC50 = 3.0 g/mL
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Table 37. Continued compounds cells activity α α 473 3 ,7 -diacetylkhivorin (440) Caco-2 IC50 = 35 ppm 473 SiHa IC50 = 54 ppm 473 MCF-7 IC50 = 69 ppm μ 665 humilinolide C (695) A-549 ED50 = 37.7 g/mL μ 665 MCF-7 ED50 = 94.1 g/mL μ 665 humilinolide D (697) A-549 ED50 = 60.6 g/mL μ 665 MCF-7 ED50 = 65.0 g/mL μ 665 HT-29 ED50 = 53.6 g/mL μ 667 erythrocarpine B (714) P388 IC50 = 6.0 g/mL μ 667 erythrocarpine C (715) P388 IC50 = 9.9 g/mL μ 667 erythrocarpine A (727) P388 IC50 = 2.0 g/mL μ 637 xylogranatin B (762) P388 IC50 = 8.9 M μ 637 A549 IC50 = 11.3 M μ 637 xylogranatin C (763) P388 IC50 = 6.3 M μ 637 xylogranatin D (764) P388 IC50 = 14.6 M μ 677 xyloccensin M (771) HCT-8 IC50 = 14.77 M μ 677 Bel-7402 IC50 = 12.81 M μ 677 BGC-283 IC50 = 8.90 M μ 677 A549 IC50 = 18.55 M μ 677 A2780 IC50 = 16.60 M μ 677 xylocarpin J (776) HCT-8 IC50 = 7.75 M μ 677 Bel-7402 IC50 = 8.22 M μ 677 BGC-283 IC50 = 8.38 M μ 677 A549 IC50 = 5.35 M μ 677 A2780 IC50 = 4.77 M μ 665 humilinolide A (793) A-549 ED50 = 64.4 g/mL μ 665 MCF-7 ED50 = 79.5 g/mL μ 665 HT-29 ED50 = 59.6 g/mL μ 665 humilinolide B (794) HT-29 ED50 = 81.1 g/mL μ 632 granaxylocarpin A (819) P388 IC50 = 9.3 M μ 675 xylomexicanin A (821)KTIC50 = 4.59 M μ 632 granaxylocarpin B (822) P388 IC50 = 4.9 M μ 448 xylogranatin C (823) CHAGO IC50 = 9.16 M μ 667 erythrocarpine D (827) P388 IC50 = 10.0 g/mL μ 667 erythrocarpine E (828) P388 IC50 = 16.0 g/mL μ 637 xylogranatin A (832) A549 IC50 = 15.7 M μ 677 xyloccensin Y (988) HCT-8 IC50 = 10.43 M μ 677 Bel-7402 IC50 = 13.55 M μ 677 BGC-283 IC50 = 9.87 M μ 677 A549 IC50 = 16.23 M μ 677 A2780 IC50 = 11.64 M μ 412 ceramicine A (1118) P388 IC50 =15 g/mL of 300 μM.435 The epimeric mixture of photogedunin (433)462 inhibition of humilinolides B (794)andD(697)atthetested and cedrelanolide I (599)571 partially inhibited photophosphor- concentration.629 ylation, H+ uptake, and noncyclic electron flow, and then 599 interfered with monocot preemergence properties, mainly energy 5.2. Biological Activities in Medicinal Use metabolism of the seeds at the level of respiration.571 In addition, an 5.2.1. Antineoplastic Activity. Most limonoids showed epimeric mixture of photogedunin inhibited seed germination, their antineoplastic activity as cytotoxicity with the IC50 values seedling growth, and root and hypocotyl/coleoptyle growth in all listed in Table 37. The cytotoxicity of ten limonoids from Turrea species assayed.949 Humilinolides A (793)andC(695) inhibited pubescens was evaluated. Of these limonoids, isoazadironolide the radicle growth of Echinochloa crus-galli with IC50 values of 99.06 (38) and turrapubesin E (276) exhibited moderate activities μ μ g/mL and 163.0 g/mL, respectively. In addition, Amaranthus against the P388 cell line, with the IC50 values of 16.0 and hypochondriacus waslesssensitiveto793 and 695 with IC50 values 12.3 μM, respectively, and none of them were active against the of 199.0 μg/mL and 215.8 μg/mL, respectively, in contrast to no A549 cells.126 Among the eight human cancer cell lines M14,
BP dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
Table 38. Inactive Meliaceous Limonoids against Tumor Cell Lines
compounds cell lines
mahonin (17)KB97 6α-acetoxyepoxyazadiradione (62) KB, NCI-H187, MCF797 toonaciliatone A (73), perforin A (535), and methyl 3β-acetoxy- SMMC-7721, HL-60, A549, SK-BR-3, PANC-1145 1-oxomelic-14(15)-enate (741) 3-deoxymethylnimbidate (339), 2,3-dihydronimbolide (347) ASK369 ohchinolide A (371), 1-O-detigloyl-1-O-benzoylohchinolal (397), HeLa S3387 1-O-detigloyl-1-O-cinnamoylohchinolal (398), ohchinolal (556) chisonimbolinins A G(378 384) HeLa, SMMC-7721390 7-deacetoxy-7α,11α-dihydroxygedunin (425) P388433 rohitukin (480) P388210 gaudichaudysolin A (492) HL-60, RPMI8226, NCI-H226, HCT116, MCF7502 cipadonoids B G(567, 1046 1050) P388544 methyl angolensate (568), mexicanolide (626), proceranolide (632), CHAGO, SW-620, KATO-3, BT-474, Hep-G2448 xyloccensins K (788), O (948), P (949) methyl 2β,3β-diacetoxy-3-deoxoangolensate (577), cineracipadesins P-388563 A F(816, 580 583, 1040) humilinolide C (695) HT-29665 xylomexicanin B (750) HeLa, HEC-1, SHIN3, HOC-2, HAC-2, HLE, U251-SP, T-98,MM1-CB, HMV-1, KT675 xylogranatin S (765) HeLa, HLE, MDA-MB-231, SW-620676 humilinolide B (794) A549, MCF-7665 granaxylocarpins A and B (819 and 840) A549632 xylomexicanin A (821) HeLa, HEC-1, SHIN3, HOC-2, HAC-2, HLE, U251-SP, T-98,MM1-CB, HMV-1675 xylocarpanoid A (825) MDAMB-21, SW-620634 granaxylocarpins C E(830, 984, and 981) P388, A549632 moluccensins H J(963, 967, and 968) BT474, CHAGO, Hep-G2, KATO-3, SW-620723 trichiliton A (997) HL-60, SMMC-7721, A-549, SK-BR-3651 cipatrijugins A D(1023 1026), cipadesin A (1051) A549, K562735 trichilins A and B (1036 and 1043) HL-60, BEL7402, Hela, MCF-7731 cipadonoid F (1049) HT29, HCT116, SW480, MDA-MB-231, MDA-MB-468, MCF-7, SMMC-7721, BEL-7402, MKN28, MKN45, SGF-7901, KB, RH30, SK-OV-3, Hela, HL-60, K562, K562/A02544
NCI-H23, SF-539, PC-3, SW620, KM12, UO-31, and ACHN, its antiproliferative and apoptosis inducing effects. The nim- the most sensitive cells according to the dose response profiles bolide-induced growth inhibition and cell cycle arrest of HT-29 to 29-deacetylsendanin (157) were SF-539 and PC-3 which had were not associated with cellular differentiation, but instead with μ 957 GI50 (growth inhibition of 50%) values of less than 0.010 g/ the time-dependent up-regulation of p21, cyclin D2, Chk2. mL.203 12α-Hydroxyamoorastatin (166), 12α-acetoxyamooras- Methyl angolensate (568) inhibited growth of T-cell leukemia tatin (167), and 12α-hydroxyamoorastatone (173) were all and chronic myelogenous leukemia cells in a time- and dose- significantly cytotoxic to the human tumor cell lines of A-549, dependent manner, which involved the induction of apoptosis by SK-OV-3, SK-MEL-2, XF-498, and HCT-15. Of these com- triggering the intrinsic pathway.958 pounds, 167 was the most active with ED50 values from 0.7 Nimbolin B (366) was moderately active in the brine shrimp to 40 ng/mL.213 In the human glioblastoma cell lines of lethality test, and it was significantly cytotoxic against HT-29 with 3 μ 384 G-28, G-112, and G-60, azadiracthin (292) induced a significant an ED50 value of <10 g/mL. Volkensinin (1057)showed μ suppression of the binucleation index of 11, 8, and 24% weak bioactivity in BST with an LC50 value of 57 g/mL, and it was respectively.950 In comparison with azadirachtin (292), nimbo- generally but weakly cytotoxic against six human tumor cell lines, lide (345) was found to be a more potent antiproliferative and giving ED50 values of 27.90, 28.35, 33.56, 29.56, 8.43, and 28.51 apoptosis-inducing agent and offered promise as a candidate μg/mL against A-498, PC-3, PACA-2, A-549, MCF-7, and HT-29, agent in multitargeted prevention and treatment of cancer.951,952 respectively.744 Gedunin (416) showed anticancer activity via in- The cellular and molecular mechanism by which 292 and 345 act hibition of the 90 kDa heat shock protein (Hsp90) folding machin- against the HeLa cell line was investigated, and it was concluded ery and caused the degradation of Hsp90-dependent client proteins that both compounds simultaneously arrest the cell cycle and similarly to other Hsp90 inhibitors.959 Nymania 1 (522)showed target multiple molecules involved in mitochondrial apoptosis, reproducible, significant, and selective activity against the DNA and thus offer immense potential as anticancer therapeutic repair-deficient RS322YK yeast strain, whereas Tr-B (479)exhi- drugs.953 Treatment with nimbolide (345) resulted in dose bited moderate but selective activity, suggesting that they might have and time-dependent inhibition of growth of BeWo cells,954,955 cytotoxic activity mediated by a DNA-damaging mechanism.192 HL-60, U937, THP-1 and B16,956 suggesting that 345 has Aphanastatin (142), together with amoorastatin (165) and immense potential in cancer prevention and therapy based on 12α-hydroxyamoorastatin (166), was reported as showing
BQ dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW significant antineoplastic activity, but no data were provided.197 promising antibacterial activity against all the eight tested multi- On the negative side, many limonoids were found to be inactive ple-drug-resistant (MDR) bacterial strains tested, this limonoid against specific tumor cell lines. These results are listed in skeleton may be useful as a template for the synthesis of more Table 38 in detail. potent structural analogs.649 2-Hydroxy-3-O-isobutyrylprocera- The presence of both a C-19/28 lactol and a C-14/15-epoxide nolide (636) and 2-hydroxyfissinolide (649) exhibited antimi- group was found to be especially important for pronounced crobial activity against Micrococcus luteus ATCC 9341 with MIC inhibition of the P-388 lymphocytic leukemia system in vitro cell values of 50 and 12.5 μg/mL, respectively.458 Moluccensins H J line, and substitution of an A-ring α,β-unsaturated ketone (963, 967, and 970) were tested for antibacterial properties (3-oxo-1-ene) for the lactol led to diminished activity, while reduc- against Staphylococcus aureus, S. hominis, S. epidermidis, Entero- tion of the olefin caused complete loss of activity.845 Most coccus faecalis, Escherichia coli, Pseudomonas aeruginosa, Proteus trichilin-class limonoids with a C-14/15-epoxide and a C-19/ vulgaris, and Salmonella typhimurium, but only 967 displayed 28 acetal bridge exhibited strong cytotoxicity against P388 weak activity against S. hominis and E. faecalis with a MIC at cells.196,205,213,221,226,433 Similarly, trichilin H (145) and toosen- 256 μg/mL.723 6-Acetoxy-7α-hydroxy-3-oxo-14β,15β-epoxy- danin (167), which have C-14/15 epoxide moieties, showed meliac-1,5-diene (69) exhibited strong antibacterial activity highly cytotoxicity against KB cell, whereas toosendanal (185) against Salmonella paratyphi and Vibrio cholerae but no data were 142 and meliatoxin B1 (177), possessing C-15 keto structure, did not provided in the original paper. fi 211 show any signi cant level of cytotoxicity. The ED50 values of Neither xyloccensin I (769) nor xyloccensin J (770) was active 12α-hydroxyamoorastatin (166) (0.002 μg/mL) and amooras- in a broad screening effort which included assays for antimicro- tatone (172)(30μg/mL) further supported the supposition that bial, antiviral, anthelmintic, and antikinase responses.626 The six the C-14β/15β epoxy was a definite requirement for growth limonoids grandifolide A (775), anthothecanolide (779), 3-O- inhibition of P388 cell lines.210 The cytotoxic activity against acetylanthothecanolide (780), 6S-hydroxykhayalactone (999), P388 cells of the five melicarpinin derivatives (321 324 and 327) khayanolide A (1002), and deacetylkhayanolide E (1008), were with a C-3 acetate was decreased, and with a C-20 acetate it was all inactive in an antimicrobial assay against Escherichia coli, almost zero.345 The more pronounced cell growth inhibitory Staphylococcus aureus, S. epidermidis, and Candida albicans with activity of the structurally simpler amoorastatin (165) as com- MIC values of greater than 50 μg/mL.679 pared to aphanastatin (142) suggested that the 1α-acetoxy, The antiviral activity of limonoids was also investigated. 29- 2α,12α-dihydroxy, and 28-methylbutyryl groups of 142 were Deacetylsendanin (157) showed antiviral activity by inhibiting unnecessary and indeed might even lessen inhibition of neoplas- the replication of HSV-1, reducing the synthesis of HSV-1 TK, tic (P388) cell growth.229 In addition, the α,β-unsaturated enone and leading to the formation of defective nucleocapsids.963 moiety or its equivalent conjugated system in the A-ring, the C-7 Dysoxylins A D(205 208) showed anti-RSV (respiratory acetyloxy/chloroacetyloxy or keto group on the B-ring, and the syncytial virus) activities with the EC50 values in the range of furan moiety were the structural requirements for the high 1.0 4.0 μg/mL in cytopathic effect inhibition and plaque activity of azadirone (1), which was a potent cytotoxic agent reduction assays.255 1-Cinnamoyl-3,11-dihydroxymeliacarpin with good in vitro and in vivo activity.83 (312) displayed a potent antiviral action affecting both DNA 5.2.2. Antimicrobial Activity. Among the five limonoids and RNA viruses by the same mechanism of action, and also dysobinin (11), azadiradione (12), mahonin (17), epoxyazadir- comprised an additional biological property consisting of altering adione (60), and 6α-acetoxyepoxyazadiradione (62), only 12 the NF-kB pathway, which suggested an eventual role as an anti- fl 337 exhibited a strong antibacterial effect against Mycobacterium in ammatory agent. In addition, 312 showed IC50 values of 6 tuberculosis, giving a MIC of 6.25 μg/mL.97 6-Acetoxy-11α- μM and 20 μM for vesicular stomatitis (VSV) and herpes simplex 336 hydroxy-7-oxo-14β,15β-epoxymeliacin-1,5-diene-3-O-α-L- (HSV-1) viruses, respectively. 312 exerted its antiviral action rhamnopyranoside (104) had more positive antibacterial activity on the endocytic and exocytic pathways of VSV by pre- and post- than streptomycin at the concentrations tested against Vibrio treatment, respectively.964 In addition to its antiviral effect, 312 cholerae, Klebsiella pneumoniae, Salmonella typhimurium, and would be acting as an immunomodulating candidate, which Escherichia coli.176 1-Cinnamoyltrichilinin (192), trichilinin B would be responsible for the improvement of murine HSK (195), and 12-ethoxynimbolinin C (385) exhibited significant already reported.965 The delay on glycoprotein transport caused antibacterial activity against Porphyromonas gingivalis ATCC 33 by 312 would account for the strong inhibition on virus multi- 277, with MIC values of 15.6, 31.5, and 31.3 μg/mL, respec- plication without interfering with the bioactivity of cellular tively.186 No mutagenicity of nimbolide (345) was detected by glycoproteins.966 Besides, for 6-O-acetyl-2-hydroxyswietenine Ames’ test using both TA98 and TA100 tested strains. However, (688), 2-hydroxyswietenine (689), 2-hydroxyswietemahonolide at 0.875 mg/disk it exhibited antibacterial activity against (797), swietemahonin G (806), and 6-O-acetylswietemahonin G the three strains Staphylococcus aureus, S. coagulase (+), and (807), their antiviral activity against HIV-1 replication was tested S. coagulsae (-) out of a total of 3/17 strains.962 The results by their inhibition of virus-induced cytopathicity in MT-4 cells, obtained by Kraus et al. showed that 345 inhibited Pseudomonas and none of them showed activity at 100 μg/mL.630 stutzeri even at a concentration of 0.5 μg/spot.322 3α,7α-Didea- 5.2.3. Antiprotozoal Activity. Omar et al. reviewed the cetylkhivorin (440) showed stronger antimicrobial activity than traditionally used antimalarials from Azadirachta indica, Lansium methyl 6-hydroxyangolensate (569)againstRhizopus stolonifer.447 domesticum, and Cedrela odorata, and presented the improve- Methyl angolensate (568) displayed growth inhibition against ment of the activity in vivo of gedunin (416).967 Gedunin (416) Proteus vulgaris with an inhibition zone of 14.1 mm, followed by has been proved to be the most active limonoid according to Klebsiella pneumoniae with 13.5 mm, Staphylococcus aureus with miscellaneous antimalarial tests up to now. It had IC50 values 13.3 mm, Escherichia coli with 12.8 mm, and Salmonella typhi- against Plasmodium falciparum of 3.1 and 0.14 μM using [3H]- murium with 12.0 mm.947 As swietenolide (638) and 2-hydroxy- hypoxanthine and 48 h culture assays, respectively.968 Its anti- 3-O-tigloylswietenolide (642) have the same skeleton, and show malarial activity was qualitatively assessed in vitro with an IC50 of
BR dx.doi.org/10.1021/cr9004023 |Chem. Rev. XXXX, XXX, 000–000 Chemical Reviews REVIEW
∼ μ μ ( μ fi 1 M after 48 h exposure (0.3 M after 96 h), which is roughly (IC50 69 13 M), and 2,6-dihydroxy ssinolide (668) had an 429 ( equivalent to quinine. Among the 27 limonoids tested, 416 IC50 of 0.12 0.08 mM against P. falciparum and an IC50 of showed the most potent activity against P. falciparum with an greater than 0.20 mM against L. major.601 Walsuronoids A and B μ IC50 value of 0.72 g/mL, but it did not inhibit P. berghei in a (1054 and 1058) showed 40% inhibition of P. falciparum at a 4-day test in mice at doses of 90 mg/kg/day.500 The five concentration of 40 μM.739 limonoids, gedunin (416), 1-deacetylkhivorin (435), 7-deacetyl- The in vitro trypanocidal activity of six mexicanolide- and khivorin (437), methyl angolensate (568), and 6-acetylswiete- gedunin-class limonoids on trypomastigote forms of Trypanoso- nolide (645) showed antimalarial activity with IC50 values ma cruzi was less than the activity of oleanane- and tirucallane- between 1.25 and 9.63 μg/mL, among which the most active, type triterpenes.132 Ceramicines B D(222 224), which con- 416, had an additive effect with chloroquine.436 When orally tain a tetrahydrofuran ring, showed potent antiplasmodial activity, administered at 50 mg/kg/d for 4 days, 416 suppressed the whereas ceramicine A (1118) without the tetrahydrofuran ring parasitemia level by 44%, and synergism with the cytochrome exhibited relatively weak activity.262 From the data obtained with P450 inhibitor dillapiol or addition of a stable methoxy group at the modified furan moieties of gedunin (416), it seemed that this the C-7 position increased its antimalarial activity.969 section of the molecule was less important for antimalarial Among the four limonoids nimocinol (7), meldenin (243), activity than the α,β-unsaturated ketone in ring A and the isomeldenin (244), and nimbandiol (1101), 243 was the most 7-acetate function in ring B.432A comparison of the activities of μ active with IC50 value of 5.23 g/mL against a chloroquine- methyl angolensate (568) and methyl 6-hydroxyangolensate resistant Plasmodium falciparum strain.270 All limonoids of (569) suggested that the addition of a hydroxyl group at C-6 dysobinin (11), azadiradione (12), mahonin (17), epoxyazadir- decreased the antimalarial activity considerably.100 adione (60), and 6α-acetoxyepoxyazadiradione (62) had an 5.2.4. Others. Dysobinin (11) showed general CNS-depres- ff 66 inhibitory e ect against P. falciparum with IC50 values ranging sant action and mild anti-inflammatory activity. All of azadir- from 2.06 to 6.31 μg/mL.97 Azadiradione (12), domesticulides adione (12), 7-acetyl-16,17-dehydro-16-hydroxyneotrichilenone B D(562, 589, and 590), methyl angolensate (568), methyl (23), epoxyazadiradione (60), 17-epi-17-hydroxyazadiradione 6-acetoxyangolensate (570), dukunolide C (616), and 6-acetox- (78), 7-deacetylgedunin (421), and nimolicinol (451) exhibited ymexicanolide (631) showed antimalarial activities against marked anti-inflammatory activity (ID50 values 0.09 0.26 mg/ μ 70 α P. falciparum with IC50 values of 2.4 9.7 g/mL, and among ear) against TPA-induced inflammation. 6 -Acetoxyepoxya- these 589 was the most active.100 Anthotechol (84) showed zadiradione (62), gedunin (416), 6α-acetoxygedunin (418), potent antimalarial activity against P. falciparum with IC50 values 7-deacetoxy-7-oxogedunin (423), andirobin (556), and methyl of 1.4 and 0.17 μM as measured by two different assays.968 angolensate (568)ofCarapa guianensis oil were responsible Ceramicine B (222) had potent in vitro antiplasmodial activity for the antiedematogenic and analgesic effects which were μ against P. falciparum 3D7 with an IC50 value of 0.23 g/mL, dependent on blockade of signaling mechanisms triggered by while ceramicines C and D (223 and 224) exhibited moderate histamine, bradykinin, and PAF.975 In addition, these limo- μ μ activity with IC50 values of 2.38 g/mL and 2.15 g/mL, noids inhibited zymosan-induced arthritis in mice via the respectively.262 Trichirubine A (226) had significant antimalarial impairment of TNF-α,IL-1β, and CXCL8/IL-8 generation, μ 263 k 976 activity against P. falciparum with an IC50 value of 0.3 g/mL. as well as the NF- B signaling pathway. Isochuanliansu A single dose of 292 was sufficient to give the insect host- (179)and1-O-tigloyl-1-O-debenzoylohchinal (344)werethe Rhodnius prolixus, a permanent resistance against its reinfection active constituents contributing to the anti-inflammatory and with Trypanosoma cruzi and to block the ecdysis for a long analgesic effects of the fruit of Melia toosendan.235 The data time.970 Fifth-instar larvae of Rhodnius prolixus, Triatoma infes- provided by Thoh et al. suggested that azadirachtin (292) tans, and Dipetalogaster maximus infected with different clone/ modulated cell surface TNFRs thereby decreasing TNF- strains of Trypanosoma cruzi displayed drastic inhibition of induced biological responses, which might be beneficial for trypanosome development when treated with 292, which might anti-inflammatory therapy.977 Among the eleven limonoids act directly on gut physiology and/or indirectly through the isolated from Swietenia macrophylla,6-O-acetylswietemaho- neurosecretory system.971 Jones et al. demonstrated blockage of nin G (807) showed the most effective anti-inflammatory ( μ the development of the motile male malarial gamete by azadir- activity (IC50 = 27.6 1.7 M) against fMLP-induced super- achtin (292), and changes in the hemiacetal group at C-11 in the oxide anion generation.653 molecule resulted in a loss of activity.972 In addition, 292 Toosendanin (167), which itself was not able to form ion disrupted formation of organized microtubule arrays during channels in lipid bilayers, increased Ca2+ conductance related to microgametogenesis of P. berghei and specifically disrupted the the intrinsic channel activity.978 167 not only had different effects patterning of microtubules into more complex structures, such as on various subtypes of calcium channels,979 but also had an mitotic spindles and axonemes.973 Nimbolide (345) inhibited P. inhibitory effect on the inward rectifier potassium channel in an falciparum in culture with moderate potency, giving an EC50 of excised inside-out patch of the neuron under a symmetrical 0.95 mg/mL.974 7-Deacetylgedunin (421) and 7-deacetoxy-7- 150 mM K+ condition.980 It inhibited the activity of small- oxogedunin (423) exhibited good antiprotozoal activity against conductance calcium-activated potassium channels by significant Trypanosoma brucei rhodesiense, T. cruzi, Plasmodium falciparum, concentration-dependent reduction of the open probability and and Leishmania donovani, suggesting a lack of specificity for a open frequency, and these effects were partially reversible.981 protozoal target.443 Among mexicanolide (626), febrifugin Moreover, 167 did not selectively affect acetylcholine release, but (694), cipadesin (703), and cipadesin A (815), the last, with probably acted on a common mechanism responsible for trans- μ ff an IC50 value of 136.1 M, showed more appreciable trypano- mitter release at di erent synapses by interfering with the cidal activity against Trypanosoma cruzi.643 Fissinolide (648) was proteins involved in fusion and resulting in diffusion of the slightly active against chloroquine resistant strains of P. falcipar- vesicular contents into the cytoplasm and blockade of normal ( μ 982 um (IC50 48 3 M) and promastigotes of Leishmania major exocytosis.
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Salannin (332) showed a significant protective activity on BIOGRAPHIES aspirin induced gastric lesions at oral doses of 10, 20, and 50 mg/kg. At 0.5 and 0.25% concentrations, 332 also showed spermicidal activity against human spermatozoa.983 H+ K+-ATPase activity in vitro was significantly inhibited by gedunin (416) and photo- μ gedunin (433) with IC50 values of 58.86 and 66.54 g/mL, respectively, confirming their antisecretory activity as compared μ 427 to the IC50 value of omeprazole (30.24 g/mL). Methyl angolensate (568) produced its antiulcer activity by inhibition of gastric acid secretion,984 exerted significant spasmolytic activ- ity through concentration dependent inhibition of smooth muscle and reduced the propulsive action of the gastrointestinal tract in mice,985 reduced spontaneous motor activity in mice, prolonged the duration of pentobarbital sleeping time, and attenuated amphetamine-induced stereotype behavior in rats.986 Among the limonoids tested (swietenolide (638), 3-acetyls- wietenolide (643), swietenine (677), swietemahonin A (800), and swietemahonin E (804)), when the final concentration of Qin-Gang Tan was born in Sichuan, China, in 1977. He received PAF and sample were 7.5 10 8 M and 100 μg/mL, respec- his B.Sc. degree from Southwest Forestry College in 2000, M.S. tively, 800 showed the strongest anti-PAF activity with an degree from Yunnan University of Traditional Chinese Medicine inhibition of 97.4% against rabbit platelet aggregation.652 In in 2006, and Ph.D. degree from State Key Laboratory of μ another test, 800 showed an IC50 value of 40.3 g/mL against Phytochemistry and Plant Resources in West China, Kunming PAF-induced aggregation of rabbit platelets in vitro, comparable Institute of Botany, Chinese Academy of Sciences in 2009. Now to that of swietemahonin D (803).987 he is a lecturer in Natural Products Chemistry Department at Penido et al. demonstrated that in mice the inhibition of Guilin Medical University. His research interests include the allergic eosinophilia by 6α-acetoxyepoxyazadiradione (62), ge- structure and biological significance of secondary metabolites in dunin (416), 6α-acetyoxygedunin (418), 7-deacetoxy-7-oxoge- the Traditional Chinese Medicine and ethnopharmacol system. dunin (423), andirobin (556), and methyl angolensate (568) was correlated with the inhibition of CCL11/eotaxin and IL-5 generation through impairment of the NF-kB signaling path- way.988 29-Deacetylsendanin (157) was found to promote slightly the drug metabolizing enzyme activities and decreased serum transaminase activities, which were elevated by CCl4 intoxication.204 TS3 (221) increased chloride conductance in epithelial cells to an extent comparable to genistein, a known cystic fibrosis transmembrane conductance regulator.261 In a similar bioassay, rubralins A and B (262 and 263) showed μ 281 moderate inhibitory activity with IC50 values of 30 50 M. Rubrins A G(518-524), with the hemi ortho ester A-ring moiety which is crucial to potency, showed potent inhibitory activity in the LFA-1:ICAM-1 mediated cell adhesion assay with IC50 values of 10 25 nM.504 Oral administration of swietenine (677) at 25 and 50 mg/kg body weight per day to diabetic rats Xiao-Dong Luo (born 1970) is a professor of natural products was found to possess significant dose dependent hypoglycemic and hypolipidemic activity in type 2 diabetic rats.662 The con- chemistry at State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese tractile response induced by humilinolide A (793) could be Academy of Sciences. He received his B.Sc. degree in Applied mediated by estrogens, probably by occupancy of some receptors in myometrial plasma membranes to induce uterotonic response, Chemistry from East China University of Sciences and Technology 684 (1991), and Ph.D. degree in Phytochemistry from Kunming Insti- which might be estrogen-dependent. Owing to the low DPPH tute of Botany, CAS (1999). He worked as an assistant engineer in free radical scavenging activity of swietephragmins H and I (945 Yunnan Baiyao Pharmaceutical Corporation (1991), Postdoctoral and 946), the IC50 values could not be determined in the study 717 research fellow (2001) in Lehman College, City University of New proposed by Tan et al. In comparison with pentoxifylline as a York, and a visiting scientist (2005) in Chemistry Department, standard, the antisickling activity of methyl 1α,2β,3α,6,8α,14β- 10,30 1,4 Oxford University. He is interesting in discovery and development hexahydroxy-[4,2,1 ,1 ]tricyclomeliac-7-oate (1014) was of natural bioactive compounds. During his research career, he has much higher at any concentration and incubation condition 728 published over 90 scientific papers in international journals. Besides, without altering significantly the corpuscular indices. his group developed a market neem pesticide and finished pre- clinical trials of a new natural medicine in China. AUTHOR INFORMATION Corresponding Author ACKNOWLEDGMENT *Phone: 86-871-5223177. Fax: 86-871-5150227. E-mail: xdluo@ The research related to this review was supported by Natural mail.kib.ac.cn. Science Foundation of China (30000213, 30370160, 30670214),
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